Clinical subtypes, histological features and associated comorbidities
Different clinical subtypes of psoriasis exist with psoriasis vulgaris, the commonest type of
psoriasis, accounting for 90 % of all cases. About 50 % of psoriasis patients have psoriatic nail
disease with nail pitting as the most common change. Psoriatic arthritis is a seronegative
inflammatory arthritis with a prevalence of up to 25 % 8 and in the vast majority (90 %) of
psoriasis patients with psoriatic arthritis, the skin manifestations precede arthritis.
Psoriasis is thought to be a complex condition resulting from a combination of genetic
predisposition and environmental triggers. The acute forms of psoriasis, guttate and generalised
pustular psoriasis (von Zumbusch psoriasis), are both associated with infections. The former
usually occurs about 2 weeks after a b-haemolytic streptococcal infection such as tonsillitis or
pharyngitis, or a viral infection. Apart from infection, other triggering factors which may elicit
psoriasis in genetically predisposed individuals include trauma (Koebner phenomen) 9, HIV
infection 10, hypocalcaemia in generalized pustular psoriasis 11, psychogenic stress 12,13 and
certain drugs including lithium, beta-blockers, antimalarials, interferon, NSAIDs and rapid
tapers of high dose corticosteroids 14. Increased alcohol consumption and smoking have been
associated with psoriasis but neither has been shown to be a major risk factor.
The 3 main histological features of psoriasis are epidermal hyperplasia, dilatation and
proliferation of dermal blood vessels and accumulation of inflammatory cells, particularly
neutrophils and T lymphocytes in the dermis. It now transpires that the first two features are
caused by inflammatory cell infiltrates. The increased vascularity in the dermis seen
histologically is driven by angiogenic factors. One of these factors, vascular endothelial growth
factor (VEGF), is found at high levels in psoriasis plaques 15. The interaction between VEGF
and the angiopoietin/Tie signalling pathway is modulated by tumour necrosis factor a (TNFa),
a key pro-inflammatory cytokine in psoriasis 16,17.
Psoriasis is also associated with a number of systemic disorders 2 including Crohn's disease,
diabetes mellitus (notably type 2) 18, metabolic syndrome 19, obesity, cardiovascular disease 20, depression 21 and cancer. It is uncertain whether cancers particularly lymphoma and skin
cancer, are related to psoriasis or to its treatment. Psoriasis has been identified as an independent
risk factor for cardiovascular disease 22. Potential mechanisms may include the presence of
circulating pro-inflammatory factors and endothelial activation 22.Journey in understanding the immunopathogenesis of psoriasis
Genetics of psoriasis
A complete overview of the genetics of psoriasis is beyond the scope of the current article but
has been extensively reviewed elsewhere 23,24. Twin and family studies have shown that
psoriasis has a strong genetic component although the inheritance pattern is still unclear. 71 %
of patients with childhood psoriasis have a positive family history 25. Siblings 26 and first-
degree relatives 27 of psoriasis patients show a four-fold or more increased risk in developing
psoriasis. Analysis of concordance rates in twin studies 28-31 show a threefold increased risk
of psoriasis in monozygotic twins compared to dizygotic twins, being approximately 72 % and
15-23 % respectively for northern European individuals, and 35 % and 12 % respectively for
Australian individuals. These data further support genetics as a major influence in psoriasis.
At least ten chromosomal loci have been identified showing statistically significant evidence
for linkage to psoriasis (PSORS 1-10). However, the only region that has consistently been
identified in genetic screens of families with psoriasis is the major-histocompatibility complex
(MHC) region on chromosome 6 named PSORS1 32,33 and markers within this region have
repeatedly been shown to have the greatest association with psoriasis in different genome wide
NIH-PA Author Manuscript NIH-PA Author Manuscript
NIH-PA Author Manuscript
association scans 34,35. This region is considered to be responsible for up to 50 % of genetic
susceptibility to psoriasis. Within PSORS1 is the human leukocyte antigen-C (HLA-C) gene
which is the strongest candidate gene for psoriasis identified to date 32, with its allele HLA-
Cw6 (HLA-Cw*0602) shown to be the predominant risk allele. A new psoriasis susceptibility
gene ZNF313/RNF114, which may regulate T cell activation through ubiquitin ligase activity,
has been identified 34. This further supports the notion that multiple gene products share a role
in the immune regulation of psoriasis, contributing to disease pathogenesis. Other novel
psoriasis susceptibility genes that have been identified from genomewide association scans
have been summarized in a recent review 1 and include the IL-23R, CDKAL1 and the IL-4/
IL-13 gene cluster 1.
HLA-Cw6 and psoriasis
HLA-Cw6 is seen in up to 60 % of psoriasis patients compared to 15 % in the general
population. Individuals carrying this allele have a 10-20-fold increased risk of developing
psoriasis 36. A dosage effect of HLA-Cw*0602 has been observed, where homozygous
individuals have a 2.5-fold increased risk of developing psoriasis compared to HLA-Cw6
heterozygous individuals 37. Homozygous individuals also experience an earlier onset but
disease severity is not affected 37. The HLA-Cw6 allele is present in 90 % of patients with
early onset psoriasis, in 50 % of those with late onset psoriasis, and only 7.4 % of a control
population. HLA-Cw6 positive and negative psoriasis patients may exhibit distinctive clinical
phenotypes. Some clinicians have designated patients with early onset psoriasis, a positive
family history of psoriasis and the expression of HLA-Cw6 as having Type I psoriasis and
those with late onset disease, no family history and a lack of expression of HLA-Cw6 as Type
II psoriasis 38. Guttate psoriasis, both acute onset and persistent eruptive subtypes, are mostly
confined to HLA-Cw6 positive patients. Meanwhile, psoriatic nail disease, palmoplantar
pustulosis and psoriatic arthritis are more common in HLA-Cw6 negative patients 39,40. Apart
from significantly earlier disease onset, HLA-Cw*0602 is associated with more widespread
and recurrent psoriasis 39. Partial or total remission during pregnancy is much more frequent
in HLA-Cw*0602 positive women whilst HLA-Cw*0602 negative women are more likely to
have unchanged or worsening psoriasis during pregnancy 39. Koebner's phenomenon is also
more common in HLA-Cw6 positive patients 39,40.
Gene to function perspective on HLA-Cw6
The strong association of HLA-Cw6 with psoriasis further supports psoriasis as an immune-
mediated disorder. Despite this strong association, the functional role of HLA-Cw6 remains
unknown. Both the adaptive and the innate immune systems are important in defence against
pathogens, the former generates a highly specific response for a particular pathogen whilst the
latter confers immediate non-specific defence against infection. Figure 1 illustrates that HLA-
Cw6 may exert its effect via the adaptive or the innate immune system. HLA-Cw6 may act via
the adaptive immune system by its antigen presenting capacity. This hypothesis is supported
by the fact that guttate psoriasis, which is strongly associated with HLA-Cw6, is triggered by
streptococcal pharyngitis 41,42. HLA-Cw6 may also exert an innate immune response via its
interaction with a class of killer immunoglobulin-like receptors (KIRs) expressed on natural
killer (NK) and natural killer T (NKT) cells, which are important components of the innate
immune system and are implicated in the pathogenesis of psoriasis 43. NK cells produce
predominantly IFN-g and may cause cytolysis of target cells. NK cell activity is up-regulated
by IL-2, IL-12 and IL-15; which are all found at increased levels in psoriatic plaques. NK cells
can mediate both activating and inhibitory immune responses as they express both activating
and inhibitory killer immunoglobulin-like receptors. KIRs recognise different types of HLA-
C molecules leading to either an overall activating or inhibitory immune response. KIRs have
been associated with psoriasis and psoriatic arthritis 44. HLA-Cw6 is a natural ligand for
KIR2DL1 (an inhibitory receptor) and it is possible that interaction between HLA-Cw6 and
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
KIR2DL1 would lead to aberrant function of lymphoid cells in the immunopathogenesis of
psoriasis. A better understanding of the functional role of HLA-Cw6 is important for both
elucidating the immunopathogenesis of psoriasis and development of improved treatments for
psoriasis.
Immune response
Epidermal keratinocytes are able to recruit and activate T cells. Most T cells infiltrating
psoriatic skin are divided into T helper 1 (Th1; CD4 +) and T cytotoxic (Tc1; CD8 +) subsets 45. Two further T cell subtypes, Th17 cells 46 and regulatory T cells (Treg) 47 have been
identified as important contributors to the pathogenesis of autoimmune diseases including
psoriasis. Figure 2 illustrates the different T cell subtypes implicated in psoriasis. Involvement
of both innate (keratinocytes, dendritic antigen-presenting cells, neutrophils, macrophages,
natural killer (NK) and natural killer T (NKT) cells) and adaptive (CD4+ and CD8+ T
lymphocytes) immune responses are important in mediating the inflammatory cascade 1,48 and
this is summarized in figure 3.
Characterization of cells and cytokines showed that elevated levels of T helper (Th) 1 cytokines
IFNg, T N F a and IL-12 are present in psoriasis, but not the T helper (Th) 2 cytokines IL-4,
IL-5 or IL-10 which appeared to be protective against psoriasis. The use of Th2-type cytokines
IL-4 49 and IL-10 50 in clinical trials as treatment for psoriasis suggest that a shift of the cytokine
milieu from Th1 to Th2 response may reverse psoriasis inflammation. These observations led
to the view that psoriasis is a Th 1-type disease 51. The crucial role of TNFa in psoriasis has
become evident from three distinct TNFa inhibitors etanercept 52, infliximab 53 and
adalimumab 54 which block the interaction of soluble TNFa with TNFa receptors on target
cells and are highly effective in the treatment of psoriasis. By studying the progressive changes
in inflammatory cytokines and chemokines induced by etanercept in psoriatic lesions, it has
been suggested that TNFa may strongly regulate early cytokine production and support the
inflammation driven by IFNg and the signal transducer and activator of transcription (STAT)
pathways, thereby encouraging chemokine production that regulates T cells and DC
interactions in the skin 7. TNFa has been linked to fatigue and depression 55 which are co-
morbidities associated with psoriasis and TNFa receptors have been detected in the central
nervous system. 55 Hence biological therapies targeting TNFa may also improve these psoriasis
associated co-morbidities in the long term 56.
Role of T cells
Until the 1990s, psoriasis was thought to be a disease of disordered keratinoctye proliferation
and differentiation 57 especially as epidermal hyperplasia was the most prominent clinical and
histological feature. This initial view of psoriasis resulted in the use of antimetabolites
including methotrexate which limit epidermal hyperproliferation. However, subsequent
evidence from clinical studies, in vitro and in vivo experimental models support the concept
that psoriasis is a T cell-mediated inflammatory skin disease 51 affecting genetically
predisposed individuals and the observed epidermal hyperplasia is a result of cellular immune
infiltration. The first piece of evidence resulting in psoriasis being widely considered as a T-
cell mediated autoimmune disease came from the success of T-cell-targeted therapies such as
cyclosporin 58,59 and tacrolimus 60 in the treatment of psoriasis 61. Monoclonal antibodies
specific for CD3 and CD4, which are more selective biological T-cell antagonists, produced
clinical improvement in some patients with severe psoriasis. A pivotal study involved the
testing of interleukin-2 (IL-2)-diphtheria-toxin fusion protein in psoriasis patients 62. This
agent was proposed to selectively deplete activated T cells expressing IL-2 receptors from
psoriasis skin lesions and resulted in clinical and histopathological remission of psoriasis
vulgaris. These studies stimulated further research into the development of T-cell-targeted
drugs for psoriasis treatment. Subsequently, administration of another fusion protein, cytotoxic
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
T-lymphocyte antigen 4 (CTLA4)-immunoglobulin, was shown to reverse the clinical and
cellular features of psoriasis 63. This agent blocks T cell co-stimulation mediated by dendritic
cells (DCs) but does not directly deplete T cells. Its effectiveness indicated that continuing T-
cell co-stimulation is required to sustain psoriasis disease activity, including the excessive
infiltration of T cells and DCs into the skin 64. These clinical studies all provided evidence that
lesion-associated T cells are central to sustaining disease activity in psoriasis vulgaris. Further
evidence highlighting the importance of T cells in psoriasis pathogenesis have been reviewed 1 including the appearance of clonal T cells in psoriatic lesions 65, the development of
psoriasiform phenotype within symptomless (nonlesional) psoriatic skin after transplantion
onto the xenotransplantation AGR 129 mouse model again highlights the importance of
epidermal T cells in the development of psoriasis 66. The immune response involved in psoriasis
pathogenesis is explained further below.
The IL-23/Th17 axis
The IL-23/Th17 axis is an exciting new area in psoriatic pathology because it has led to the
development of promising new treatments for psoriasis which specifically target this axis. The
development, characterization and function of Th17 cells and the role of IL-23 in Th17-cell-
dependent chronic inflammation in psoriasis have been recently reviewed 67. Briefly, IL-23 is
a heterodimeric cytokine 68 and consists of the protein IL-23p19 combined with IL-12p40, an
IL-12 subunit. Intradermal injection of IL-23 in mice resulted in the development of a
psoriasiform phenotype with histopathological features 69. IL-23 has been shown to mediate
epidermal hyperplasia, acanthosis, hyperparakeratosis and orthohyperkeratosis via TNF-a,
IL-20R2 and IL-22 69,70. These results are supported by findings in humans including an over-
expression of IL-23p19 and IL-12p40 (precursors of IL-23) seen at the mRNA level in psoriatic
skin lesions, compared to uninvolved skin. Further data indicate that production of IL-23 occurs
at inflammatory skin sites and is mediated by tissue-resident and/or recruited immune cells,
such as dendritic cells and possibly keratinocytes 71. The pathogenic role of IL-23 in psoriasis
is strongly supported by the clinical findings that anti-TNF-a agents can reduce IL-23p19 and
IL-12p40 mRNA levels, and reduction of IL-23 level caused by cyclosporin A, UV therapy
and biological agents correlates to clinical improvements in psoriasis patients 72-74.
Transforming growth factor (TGF)-b1, IL-6 and IL-21 are all required to transform na?ve T
cells into cells expressing the unique lineage-specific transcription factor, RORC variant 2 and
IL-23 receptors with subsequent binding of IL-23 resulting in differentiation into Th17 cells.
Th17 cells in turn produce IL-17A, IL-17F, IL-22 and IL-26 which are proinflammatory
cytokines 75. These cytokines activate keratinocytes leading to hyperproliferation and further
production of proinflammatory cytokines, chemokines and antimicrobial peptides, which in
turn recruit and activate other immune cells in the inflamed skin, leading to amplification of
the inflammatory response and clinical features of the disease.
Support for a role of the IL-23/Th17 axis in psoriasis comes from whole genome studies
showing that genetic variants of the IL-23 receptor and its ligand IL12B are associated with
psoriasis 35.
Regarding the clinical relevance of the IL-23/Th17 pathway, targeting the common subunit
p40 of IL-12 and IL-23 has demonstrated clinical improvement in psoriasis. Two anti-IL-12p40
monoclonal Abs, CNTO-1275/ustekinumab and ABT-874, have been recently developed as
psoriasis treatments. Ustekinumab and ABT-874 are humanized IgG1 monoclonal antibodies
that bind to the p40 subunit of human IL-12 and IL-23 and prevent interaction with IL-12Rb1.
Phase I 76 and phase II 77,78 studies have supported the use of both antibodies as effective
treatments for moderate to severe psoriasis. The safety profile of ustekinumab in psoriasis has
been evaluated in 2 phase III studies. Of these, PHOENIX I assessed the efficacy and safety
of ustekinumab 45 and 90 mg administered subcutaneously at weeks 0, 4, and then every 12
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
weeks over 76 weeks of treatment 79. 67.1 % and 66.4 % of patients who received ustekinumab
45mg and 90mg respectively, achieved PASI-75 (improvement of PASI score by 75 %) at
week 12 compared to placebo control (3.1 %). Efficacy increased over time and maximum
effect was seen at week 24 with PASI-75 achieved in 76.1 % of patients treated with 45mg and
in 85 % of patients treated with 90mg. The observed adverse events were mild, non-life
threatening and not significantly different from the placebo group. The most commonly
reported adverse events were upper respiratory tract infections, nasopharyngitis, headache, and
arthralgia. The PHOENIX II trial 80 was conducted to further assess if dosing intensification
would increase the response to treatment in partial responder patients (between PASI-50 and
PASI-75). It was found that dosing intensification resulted in increased clinical efficacy only
in patients receiving 90mg, but not 45mg, of ustekinumab every 8 weeks (PASI-75 in 68.8 %
of patients receiving 90mg every 8 weeks versus 33.3 % of patients receiving 90 mg every 12
weeks). The incidence and type of adverse events observed did not differ between PHOENIX
I and II studies. Ustekinumab is also effective in the treatment of psoriatic arthritis 81 and this
study again confirmed that ustekinumab is well tolerated 81.
Regulatory T cells
Regulatory T (Treg) cells are characterized by their ability to suppress the activation and
proliferation of CD4+ and CD8+ effector T cells via mechanisms that either require direct
contact with antigen presenting cells 82 or by releasing IL-10 83 or transforming growth factor
beta 1 (TGF-b1) 84. Treg cells express CD4, CD25 and the specific transcription factor Foxp3.
They account for between 1-5 % of the total population of peripheral CD4+ cells. Dysfunction
of Treg cells has been implicated in the pathogenesis of autoimmune diseases such as multiple
sclerosis, rheumatoid arthritis and autoimmune polyglandular syndrome type II. In psoriasis,
Treg function and proliferation are both defective 47. This combination may result in a failure
to constrain the activation and proliferation of pathogenic T cells, contributing to the ongoing
inflammation seen in psoriasis. Hence strategies that correct Treg function or increase the
Treg:pathogenic T cell ratio may be potential treatments for psoriasis 47. Phototherapy may
induce Treg type suppressor cells as well as eliminate pathogenic T cells 85, supporting a
possible role of Treg cells in protection against psoriasis.
Contribution of animal models in understanding the roles of resident T cells in the skin and the importance of plasmacytoid dendritic cells (PDCs)
A major hindrance in studying the immunopathogenesis of psoriasis and subsequent
development of new therapies is the lack of disease relevant animal models. No naturally
occurring disorder in laboratory animals can mimic the complex phenotype of psoriasis. After
decades of research, a number of psoriasis mouse models have been developed, each with
specific advantages and shortcomings. A number of comprehensive and critical reviews of
different psoriasis mouse models have been published recently 86-88. Criteria for an ideal
psoriasis mouse model 86 should include:
1.
Display of typical psoriasis clinical features and histopathology.2.
Feature the major role of T cells, due to overwhelming evidence in the literature.3.
Psoriatic lesions should clear with well established pharmacological treatments for the disease.4.The pharmacologically validated model should reflect the clinical response in
patients. There are two main approaches to the currently available mouse models: a)
generation of mice with over-expression (transgenic) or deletion (knock out) of certain
genes and gene products in specific tissue compartments such as the epidermis and
b) xenotransplantation models involving transplantation of human skin onto NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
immunosuppressed mice to avoid graft rejection. The latter approach may overcome the problem of species difference which exists in the former approach.Although no single model is perfect, the xenotransplantation AGR 129 mouse model 89 has been instrumental in understanding the early events of the immunopathogenesis of psoriasis.AGR 129 mice are deficient in type I (A) and type II (G) IFN receptors, in addition to lacking T and B cells (RAG-2 –/–). In the AGR 129 mouse model, psoriatic phenotype develops spontaneously upon transplantation of symptomless non-lesional skin onto mice. No exogenous cells or factors are required to initiate the psoriatic lesions thereby allowing studies of early mechanisms in psoriasis immunopathogenesis. After transplantation of non-involved psoriatic skin onto the AGR 129 mouse, injection of the monoclonal anti-human CD3 antibody,which blocks T cell functions, results in inhibition of psoriasis development 89. Furthermore,application of a neutralizing anti-human TNF-a monoclonal antibody, or TNF receptor fusion protein, leads to significant reduction of T cell numbers in the graft and inhibition of psoriasis phenotype development 89. It was demonstrated that the source of TNF-a is local antigen presenting cells within the skin graft. Altogether, these data suggest that local TNF-a production is crucial for resident T cell proliferation and psoriasis development. These studies also provide evidence that local proliferation of effector T cells, rather than their recruitment,is important for induction of psoriasis.Three types of DCs (Langerhans cells, dermal DCs and plasmacytoid DCs) play important roles in psoriasis. It has been demonstrated that plasmacytoid dendritic cells (PDCs) produce IFN-a, which results in the activation of many aspects of the innate immune system and helps drive the inflammatory process in psoriasis 90. A role for IFN-a in psoriasis is supported by three observations 90. First, an activated IFN-a signalling pathway is present in psoriatic skin lesion 91,92. Secondly, continuous excessive IFN-a/b signalling results in an inflammatory skin disease in a mouse model that resembles psoriasis. Thirdly, administration of recombinant IFN-a to psoriasis patients for treatment of viral infections or tumours may worsen psoriasis. It has been demonstrated that PDCs accumulate in the skin of psoriasis patients and are activated to
produce IFN-a early in the development of psoriasis 90. PDCs are a rare cell population in
peripheral blood and secondary lymphoid organs. They are the main effector cells in executing
the antiviral activities of the innate immune system due to their unique ability to secrete large
amounts of IFN-a in response to viral stimulation through their toll-like receptor (TLR)-7 and
TLR-9. Through IFN-a production, PDCs drive the activation and expansion of the
autoimmune T cell cascade leading to psoriasis 90, hence PDCs may provide a unique link
between the innate and adaptive immune system in driving inflammation in psoriasis. In the
same study, the number of PDCs were found to be increased in both plaque lesions and the
nearby uninvolved skin of psoriasis patients but were completely absent in normal healthy skin
or inflamed skin of atopic dermatitis. Activation of PDCs was demonstrated to occur locally
in lesional psoriatic skin. IFN-a production by PDCs was increased early and transiently in the
development of psoriasis and production declined as disease progressed. Intravenous ijection
of an anti-BDCA-2 monoclonal antibody, which shared specific binding to human PDCs, led
to a > 90 % reduction of IFN-a expression in the engrafted pre-psoriatic skin, resulting in
complete inhibition of the subsequent pathogenic T cell activation and expansion and psoriatic
phenotype development. Because human PDCs from the transplanted skin do not re-circulate
in the AGR 129 mouse model, in vivo treatment with anti-BDCA-2 antibody selectively
targeted human PDCs present in the engrafted pre-psoriatic skin, thereby confirming that PDCs
represented the main IFN-a-producing cells. Administration of recombinant human IFN-a was
found to be sufficient to reverse the anti-BDCA-2-mediated inhibition of T cell expansion and
psoriasis development 90. Hence, activation of PDCs and their IFN-a production represents an
important proximal event in the psoriasis immune axis, highlighting the contribution of innate
immunity towards autoimmunity in psoriasis. The pathogenic role of PDCs in psoriasis is
further supported by the observation that the topical ILR 7/8 ligand imiquimod which activates
NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript
PDCs can exacerbate psoriasis 93. Hence therapies that target PDCs and PDC-derived IFN-a
may be valuable for both prevention and early treatment of psoriasis. IFN-a targeted therapies
may be advantageous over anti-TNF-a therapy in that its production is highly specific, both
spatially and temporally i.e. IFN-a is mainly produced by dermal PDCs during the early stage
of psoriasis development unlike TNF-a which is produced by a broad range of cells including
myeloid DCs, T cells and keratinocytes throughout different stages of psoriasis. Hence, IFN-
a targeted therapies may facilitate prevention and early treatment of psoriasis, minimizing the
need for long term administration and monitoring of existing psoriasis therapies with a number
of potential adverse side effects. PDCs and IFN-a have also been implicated in a number of
other autoimmune diseases including lupus erythematosus, rheumatoid arthritis and insulin-
dependent diabetes mellitus 94. Hence the role of PDC-induced innate activation via IFN-a
production may also provide valuable insights into the pathogenesis of other autoimmune
diseases and their treatment strategies.
Role of bacterial superantigen
Of the many environmental factors implicated in the immunopathogenesis of psoriasis, throat
infection with a-haemolytic streptococci is an external trigger that has been associated with
initiation and exacerbation of guttate psoriasis 95. However, a specific antigen responsible for
T cell activation in the skin has yet to be conclusively identified. It has been suggested that
antigen presenting cells in the tonsillar tissue may ingest bacterial wall fragments and are then
re-circulated into the skin where they may activate a T cell response, resulting in psoriatic
lesions 96. Molecular mimicry is another hypothesis where T cell clones originally generated
in response to streptococcal tonsillitis or pharyngitis are subsequently reactivated in the skin
because of a cross-reactive epitope derived from hyperproliferative epidermal keratinocytes
such as keratin 16 or keratin 1797. In a recent review 98 the close correlation between global
epidemiological variation in psoriasis prevalence with that of historical mortality from
epidemics of invasive streptococcal infections was highlighted and the authors suggested that
the psoriasis susceptibility genotype may confer protection from mortality in such epidemics.
It is postulated that changes in immunological pathways including the adaptive and the innate
immune response as well as the Th17 cell cytokine network all confer protection against
mortality during epidemics of invasive streptococcal infections by increasing efficiency in
internalizing streptococci but also increase predisposition to psoriasis development 98.
Psoriasis as an autoimmune disease
Although the presence of T-lymphocyte subsets in the early phase of the disease and the
response to T-lymphocyte-targeting therapies strongly support the hypothesis of psoriasis as
a T-lymphocyte-mediated autoimmune disease, there are still significant gaps in our
understanding of this disease. Unlike a well characterized autoimmune skin disease such as
pemphigus vulgaris, where the autoantigens and effector molecules (autoantibodies,
complement) have been extensively defined using in vitro and in vivo model systems 99, no
reproducible autoantigen has yet been defined in psoriasis.
Recent data suggest that LL37 may be a key activator of PDCs in psoriasis, converting self-
DNA into an autoimmune trigger 100. The role of PDCs as key mediators in the
immunopathogenesis of psoriasis has already been discussed. PDCs can recognise bacterial
and viral DNA through Toll-like receptors (TLR7 and TLR9) and release type 1 IFNs like IFN-
a. Under normal circumstances PDCs do not respond to self-DNA. However, in autoimmune
disease, the endogenous antimicrobial peptide LL37 may combine with and convert self-DNA
into a potent autoimmune trigger which activates PDCs into producing IFN-a. The
antimicrobial peptide LL37 is mainly expressed by keratinocytes and is released by
keratinocytes in response to injury or infection. LL37 is also released by migratory
inflammatory cells including neutrophils and is present in the dermal compartment in
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
association with PDCs. Increased expression of LL37 appears to be specific in psoriasis as it
is found to be highly upregulated in psoriatic lesions but not normal skin, uninvolved skin of
psoriasis patients or other skin disease lesions.
Data suggest that when coupled with DNA, LL37 is taken up by PDCs and these LL37:DNA
complexes then activate PDCs through TLR9 and stimulate IFN-a production 100. This may
explain how self-DNA may trigger autoimmunity in psoriasis.
a1b1 integrin and epidermal T cell accumulation
Based on the findings that expansion of skin resident T cells is important in psoriasis
development in the xenotransplantation AGR mouse model, the role of tissue-specific factors
in activation and expansion of resident T cells has been further explored 66. T cells need to
pass through the dermo-epidermal junction in order to enter the epidermis and collagen fibrils
are an essential part of the dermo-epidermal junction. The most important basement membrane
collagen is collagen IV. Long-term activation of T cells results in the expression of a receptor
for collagen IV, the heterodimeric integrin a1b1 (synonymous with CD49a-CD29 or very late
antigen 1, VLA-1). It has been shown that epidermal accumulation of a1b1-positive Th1 and
Tc1 cells correlate with psoriasis development. Blocking a1b1 with a neutralizing monoclonal
antibody prevents epidermal T cell accumulation and subsequent psoriasis development in the
xenotransplantation AGR mouse model. a1b1 expression may act as a checkpoint for entry of
T cells into epidermis with a1b1-positive epidermal T cells potentially playing an important
role in psoriatic lesion formation. Hence targeting of these integrins may offer new therapeutic
approaches in psoriasis and possibly in other autoimmune disease.Conclusion Extensive progress has been made in understanding the immunopathogenesis of psoriasis, over the last 10 years. Transfer between knowledge acquired from bench research and clinical
studies is crucial for rapid progression in both areas. The discovery of the IL23/Th17 pathway
and the subsequent development of new treatments have been major breakthroughs and better
insight into psoriasis immunopathogenesis does not only lead to improved treatments for
psoriasis but may also provide better understanding of pathological mechanisms behind other
autoimmune diseases such as Crohn's disease and better therapeutic treatments for these
diseases.
Acknowledgments
We acknowledge support by the following grant funding bodies: Medical Research Council Clinical Research Training
Fellowship, Wellcome Trust Programme GR078173MA, NIH RO1AR040065, NIHR Comprehensive Biomedical
Research Centre Guy's and St. Thomas' Hospital and King's College London, Medical Research Council UK
Programme G0601387, Dunhill Medical Trust. Dr. John Mee provided helpful discussions.
References
1. Nestle FO, Kaplan DH, Barker J. Mechanisms of Disease: Psoriasis. N Engl J Med 2009;361:496–
509. [PubMed: 19641206]
2. Henseler T, Christophers E. Disease concomitance in psoriasis. J Am Acad Dermatol 1995;32:982–6.
[PubMed: 7751469]
3. Gelfand JM, Troxel AB, Lewis JD, Kurd SK, Shin DB, Wang X, et al. The risk of mortality in patients
with psoriasis: results from a population-based study. Arch Dermatol 2007;143:1493–9. [PubMed:
18086997]
4. Nickoloff BJ, Qin JZ, Nestle FO. Immunopathogenesis of psoriasis. Clin Rev Allergy Immunol
2007;33:45–56. [PubMed: 18094946]
NIH-PA Author Manuscript NIH-PA Author Manuscript
NIH-PA Author Manuscript
5. Bowcock AM, Krueger JG. Getting under the skin: the immunogenetics of psoriasis. Nat Rev Immunol 2005;5:699–711. [PubMed: 16138103]
6. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet 2007;370:263–71.[PubMed: 17658397]
7. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature 2007;445:866–73. [PubMed: 17314973]
8. Zachariae H. Prevalence of joint disease in patients with psoriasis: implications for therapy. Am J Clin Dermatol 2003;4:441–7. [PubMed: 12814334]
9. Eyre, RW.; Krueger, GG. The Koebner response in psoriasis. In: Roenigk, HH.; Maibach, HI., editors.Psoriasis. New York: Marcel Dekker; 1984. p. 105-16.10. Reveille JD, Conant MA, Duvic M. Human immunodeficiency virus-associated psoriasis, psoriatic arthritis, and Reiter's syndrome: a disease continuum? Arthritis Rheum 1990;33:1574–8. [PubMed:2222538]11. Stewart AF, Battaglini-Sabetta J, Millstone L. Hypocalcemia-induced pustular psoriasis of von Zumbusch. New experience with an old syndrome. Ann Intern Med 1984;100:677–80. [PubMed:6546844]12. Fortune DG, Richards HL, Main CJ, Griffiths CE. What patients with psoriasis believe about their condition. J Am Acad Dermatol 1998;39:196–201. [PubMed: 9704828]13. Gupta MA, Gupta AK, Kirkby S, Schork NJ, Gorr SK, Ellis CN, et al. A psychocutaneous profile of psoriasis patients who are stress reactors. A study of 127 patients. Gen Hosp Psychiatry 1989;11:166–73. [PubMed: 2721939]14. Abel EA, DiCicco LM, Orenberg EK, Fraki JE, Farber EM. Drugs in exacerbation of psoriasis. J Am Acad Dermatol 1986;15:1007–22. [PubMed: 2878015]15. Detmar M, Brown LF, Claffey KP, Yeo KT, Kocher O, Jackman RW, et al. Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med 1994;180:1141–6. [PubMed: 8064230]16. Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, et al. Vessel cooption,regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999;284:1994–8.
[PubMed: 10373119]
17. Kuroda K, Sapadin A, Shoji T, Fleischmajer R, Lebwohl M. Altered expression of angiopoietins and
Tie2 endothelium receptor in psoriasis. J Invest Dermatol 2001;116:713–20. [PubMed: 11348459]
18. Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB, Gelfand JM. Prevalence of cardiovascular
risk factors in patients with psoriasis. J Am Acad Dermatol 2006;55:829–35. [PubMed: 17052489]
19. Sommer DM, Jenisch S, Suchan M, Christophers E, Weichenthal M. Increased prevalence of the
metabolic syndrome in patients with moderate to severe psoriasis. Arch Dermatol Res 2006;298:321–
8. [PubMed: 17021763]
20. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction
in patients with psoriasis. JAMA 2006;296:1735–41. [PubMed: 17032986]
21. Esposito M, Saraceno R, Giunta A, Maccarone M, Chimenti S. An Italian study on psoriasis and
depression. Dermatology 2006;212:123–7. [PubMed: 16484818]
22. Mrowietz U, Elder JT, Barker J. The importance of disease associations and concomitant therapy for
the long-term management of psoriasis patients. Arch Dermatol Res 2006;298:309–19. [PubMed:17021761]
23. Rahman P, Elder JT. Genetic epidemiology of psoriasis and psoriatic arthritis. Ann Rheum Dis
2005;64 2:ii37–9. discussion ii40-1. [PubMed: 15708933]
24. Capon F, Trembath RC, Barker JN. An update on the genetics of psoriasis. Dermatol Clin
2004;22:339–47. vii. [PubMed: 15450331]
25. Morris A, Rogers M, Fischer G, Williams K. Childhood psoriasis: a clinical review of 1262 cases.
Pediatr Dermatol 2001;18:188–98. [PubMed: 11437997]
26. Watson W, Cann HM, Farber EM, Nall ML. The genetics of psoriasis. Arch Dermatol 1972;105:197–
207. [PubMed: 5060862]
27. Theeuwes M, Leder RO. Hereditary insights in psoriasis. Eur J Dermatol 1993;3:335–41.NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript
28. Brandrup F, Hauge M, Henningsen K, Eriksen B. Psoriasis in an unselected series of twins. Arch Dermatol 1978;114:874–8. [PubMed: 566529]29. Duffy DL, Spelman LS, Martin NG. Psoriasis in Australian twins. J Am Acad Dermatol 1993;29:428–34. [PubMed: 8349859]30. Farber EM, Nall ML, Watson W. Natural history of psoriasis in 61 twin pairs. Arch Dermatol 1974;109:207–11. [PubMed: 4814926]31. Pisani M, Ruocco V. ‘Twin’ psoriasis in monozygotic twins. Arch Dermatol 1984;120:1418–9.[PubMed: 6541893]32. Nair RP, Stuart PE, Nistor I, Hiremagalore R, Chia NV, Jenisch S, et al. Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am J Hum Genet 2006;78:827–51.[PubMed: 16642438]33. Trembath RC, Clough RL, Rosbotham JL, Jones AB, Camp RD, Frodsham A, et al. Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis. Hum Mol Genet 1997;6:813–20. [PubMed: 9158158]34. Capon F, Bijlmakers MJ, Wolf N, Quaranta M, Huffmeier U, Allen M, et al. Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene. Hum Mol Genet 2008;17:1938–45. [PubMed:18364390]35. Capon F, Di Meglio P, Szaub J, Prescott NJ, Dunster C, Baumber L, et al. Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum Genet 2007;122:201–6. [PubMed: 17587057]36. Mallon E, Newson R, Bunker CB. HLA-Cw6 and the genetic predisposition to psoriasis: a meta-analysis of published serologic studies. J Invest Dermatol 1999;113:693–5. [PubMed: 10504461]37. Gudjonsson JE, Karason A, Antonsdottir A, Runarsdottir EH, Hauksson VB, Upmanyu R, et al.Psoriasis patients who are homozygous for the HLA-Cw*0602 allele have a 2.5-fold increased risk of developing psoriasis compared with Cw6 heterozygotes. Br J Dermatol 2003;148:233–5.[PubMed: 12588373]38. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol 1985;13:450–6. [PubMed: 4056119]39. Gudjonsson JE, Karason A, Runarsdottir EH, Antonsdottir AA, Hauksson VB, Jonsson HH, et al.
Distinct clinical differences between HLA-Cw*0602 positive and negative psoriasis patients–an analysis of 1019 HLA-C- and HLA-B-typed patients. J Invest Dermatol 2006;126:740–5. [PubMed:16439971]
40. Fan X, Yang S, Sun LD, Liang YH, Gao M, Zhang KY, et al. Comparison of clinical features of
HLA-Cw*0602-positive and -negative psoriasis patients in a Han Chinese population. Acta Derm Venereol 2007;87:335–40. [PubMed: 17598037]
41. Telfer NR, Chalmers RJ, Whale K, Colman G. The role of streptococcal infection in the initiation of
guttate psoriasis. Arch Dermatol 1992;128:39–42. [PubMed: 1739285]
42. Prinz JC. Psoriasis vulgaris–a sterile antibacterial skin reaction mediated by cross-reactive T cells?
An immunological view of the pathophysiology of psoriasis. Clin Exp Dermatol 2001;26:326–32.
[PubMed: 11422184]
43. Nickoloff BJ. Skin innate immune system in psoriasis: friend or foe? J Clin Invest 1999;104:1161–
4. [PubMed: 10545511]
44. Martin MP, Nelson G, Lee JH, Pellett F, Gao X, Wade J, et al. Cutting edge: susceptibility to psoriatic
arthritis: influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles.J Immunol 2002;169:2818–22. [PubMed: 12218090]
45. Krueger JG. The immunologic basis for the treatment of psoriasis with new biologic agents. J Am
Acad Dermatol 2002;46:1–23. quiz -6. [PubMed: 11756941]
46. McKenzie BS, Kastelein RA, Cua DJ. Understanding the IL-23-IL-17 immune pathway. Trends
Immunol 2006;27:17–23. [PubMed: 16290228]
47. Sugiyama H, Gyulai R, Toichi E, Garaczi E, Shimada S, Stevens SR, et al. Dysfunctional blood and
target tissue CD4+ CD25 high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol 2005;174:164–73. [PubMed: 15611238]
48. Gaspari AA. Innate and adaptive immunity and the pathophysiology of psoriasis. J Am Acad Dermatol
2006;54:S67–80. [PubMed: 16488332]
NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript
49. Ghoreschi K, Thomas P, Breit S, Dugas M, Mailhammer R, van Eden W, et al. Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease. Nat Med 2003;9:40–6. [PubMed: 12461524]50. Asadullah K, Docke WD, Ebeling M, Friedrich M, Belbe G, Audring H, et al. Interleukin 10 treatment of psoriasis: clinical results of a phase 2 trial. Arch Dermatol 1999;135:187–92. [PubMed: 10052405]51. Lew W, Bowcock AM, Krueger JG. Psoriasis vulgaris: cutaneous lymphoid tissue supports T-cell activation and “Type 1” inflammatory gene expression. Trends Immunol 2004;25:295–305.[PubMed: 15145319]52. Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003;349:2014–22. [PubMed: 14627786]53. Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001;357:1842–7.[PubMed: 11410193]54. Patel T, Gordon KB. Adalimumab: efficacy and safety in psoriasis and rheumatoid arthritis. Dermatol Ther 2004;17:427–31. [PubMed: 15379777]55. Simen BB, Duman CH, Simen AA, Duman RS. TNFalpha signaling in depression and anxiety:behavioral consequences of individual receptor targeting. Biol Psychiatry 2006;59:775–85.[PubMed: 16458261]56. Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, et al. Etanercept and clinical outcomes,fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III https://www.doczj.com/doc/8917403903.html,ncet 2006;367:29–35. [PubMed: 16399150]57. Krueger GG, Bergstresser PR, Lowe NJ, Voorhees JJ, Weinstein GD. Psoriasis. J Am Acad Dermatol 1984;11:937–47. [PubMed: 6389615]58. Ellis CN, Gorsulowsky DC, Hamilton TA, Billings JK, Brown MD, Headington JT, et al.Cyclosporine improves psoriasis in a double-blind study. JAMA 1986;256:3110–6. [PubMed:3023712]59. Baker BS, Griffiths CE, Lambert S, Powles AV, Leonard JN, Valdimarsson H, et al. The effects of cyclosporin A on T lymphocyte and dendritic cell sub-populations in psoriasis. Br J Dermatol 1987;116:503–10. [PubMed: 3495286]
60. Jegasothy BV, Ackerman CD, Todo S, Fung JJ, Abu-Elmagd K, Starzl TE. Tacrolimus (FK 506)–a
new therapeutic agent for severe recalcitrant psoriasis. Arch Dermatol 1992;128:781–5. [PubMed:1376102]
61. Prinz J, Braun-Falco O, Meurer M, Daddona P, Reiter C, Rieber P, et al. Chimaeric CD4 monoclonal
antibody in treatment of generalised pustular psoriasis. Lancet 1991;338:320–1. [PubMed: 1677143]
62. Gottlieb SL, Gilleaudeau P, Johnson R, Estes L, Woodworth TG, Gottlieb AB, et al. Response of
psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat Med 1995;1:442–7. [PubMed: 7585092]
63. Abrams JR, Lebwohl MG, Guzzo CA, Jegasothy BV, Goldfarb MT, Goffe BS, et al. CTLA4Ig-
mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Invest
1999;103:1243–52. [PubMed: 10225967]
64. Abrams JR, Kelley SL, Hayes E, Kikuchi T, Brown MJ, Kang S, et al. Blockade of T lymphocyte
costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig)reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes,dendritic cells, and endothelial cells. J Exp Med 2000;192:681–94. [PubMed: 10974034]
65. Menssen A, Trommler P, Vollmer S, Schendel D, Albert E, Gurtler L, et al. Evidence for an antigen-
specific cellular immune response in skin lesions of patients with psoriasis vulgaris. J Immunol 1995;155:4078–83. [PubMed: 7561119]
66. Conrad C, Boyman O, Tonel G, Tun-Kyi A, Laggner U, de Fougerolles A, et al. Alpha1beta1 integrin
is crucial for accumulation of epidermal T cells and the development of psoriasis. Nat Med
2007;13:836–42. [PubMed: 17603494]
67. Di Cesare A, Di Meglio P, Nestle FO. The IL-23/Th17 Axis in the Immunopathogenesis of Psoriasis.
J Invest Dermatol 2009;129:1339–50. [PubMed: 19322214]
NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript
68. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. Novel p19 protein engages IL-12p40to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000;13:715–25. [PubMed: 11114383]69. Chan JR, Blumenschein W, Murphy E, Diveu C, Wiekowski M, Abbondanzo S, et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med 2006;203:2577–87. [PubMed: 17074928]70. Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, et al. Interleukin-22, a T (H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 2007;445:648–51. [PubMed: 17187052]71. Piskin G, Sylva-Steenland RM, Bos JD, Teunissen MB. In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol 2006;176:1908–15. [PubMed: 16424222]72. Piskin G, Tursen U, Sylva-Steenland RM, Bos JD, Teunissen MB. Clinical improvement in chronic plaque-type psoriasis lesions after narrow-band UVB therapy is accompanied by a decrease in the expression of IFN-gamma inducers – IL-12, IL-18 and IL-23. Exp Dermatol 2004;13:764–72.[PubMed: 15560760]73. Gottlieb AB, Chamian F, Masud S, Cardinale I, Abello MV, Lowes MA, et al. TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol 2005;175:2721–9. [PubMed: 16081850]74. Haider AS, Lowes MA, Suárez-Farinas M, Zaba LC, Cardinale I, Khatcherian A, et al. Identification of cellular pathways of “type 1,” Th17 T cells, and TNF- and inducible nitric oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis. J Immunol 2008;180:1913–20. [PubMed: 18209089]75. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005;201:233–40. [PubMed: 15657292]76. Kauffman CL, Aria N, Toichi E, McCormick TS, Cooper KD, Gottlieb AB, et al. A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis. J Invest Dermatol 2004;123:1037–44. [PubMed: 15610511]
77. Krueger GG, Langley RG, Leonardi C, Yeilding N, Guzzo C, Wang Y, et al. A human
interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 2007;356:580–
92. [PubMed: 17287478]
78. Kimball AB, Gordon KB, Langley RG, Menter A, Chartash EK, Valdes J. Safety and efficacy of
ABT-874, a fully human interleukin 12/23 monoclonal antibody, in the treatment of moderate to severe chronic plaque psoriasis: results of a randomized, placebo-controlled, phase 2 trial. Arch Dermatol 2008;144:200–7. [PubMed: 18283176]
79. Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, et al. Efficacy and safety of
ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet
2008;371:1665–74. [PubMed: 18486739]
80. Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, et al. Efficacy and safety
of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet
2008;371:1675–84. [PubMed: 18486740]
81. Gottlieb A, Menter A, Mendelsohn A, Shen YK, Li S, Guzzo C, et al. Ustekinumab, a human
interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet 2009;373:633–40. [PubMed: 19217154]
82. Gondek DC, Lu LF, Quezada SA, Sakaguchi S, Noelle RJ. Cutting edge: contact-mediated
suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-
independent mechanism. J Immunol 2005;174:1783–6. [PubMed: 15699103]
83. Annacker O, Asseman C, Read S, Powrie F. Interleukin-10 in the regulation of T cell-induced colitis.
J Autoimmun 2003;20:277–9. [PubMed: 12791312]
NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript
84. Nakamura K, Kitani A, Fuss I, Pedersen A, Harada N, Nawata H, et al. TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol 2004;172:834–42. [PubMed: 14707053]85. Baadsgaard O, Salvo B, Mannie A, Dass B, Fox DA, Cooper KD. In vivo ultraviolet-exposed human epidermal cells activate T suppressor cell pathways that involve CD4+CD45RA+ suppressor-inducer T cells. J Immunol 1990;145:2854–61. [PubMed: 1976706]86. Nestle FO, Nickoloff BJ. From classical mouse models of psoriasis to a spontaneous xenograft model featuring use of AGR mice. Ernst Schering Res Found Workshop 2005:203–12. [PubMed: 15526944]87. Schon MP. Animal models of psoriasis: a critical appraisal. Exp Dermatol 2008;17:703–12. [PubMed:18557923]88. Gudjonsson JE, Johnston A, Dyson M, Valdimarsson H, Elder JT. Mouse models of psoriasis. J Invest Dermatol 2007;127:1292–308. [PubMed: 17429444]89. Boyman O, Hefti HP, Conrad C, Nickoloff BJ, Suter M, Nestle FO. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha. J Exp Med 2004;199:731–6. [PubMed: 14981113]90. Nestle FO, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boyman O, et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med 2005;202:135–43. [PubMed:15998792]91. Schmid P, Itin P, Cox D, McMaster GK, Horisberger MA. The type I interferon system is locally activated in psoriatic lesions. J Interferon Res 1994;14:229–34. [PubMed: 7861026]92. van der Fits L, van der Wel LI, Laman JD, Prens EP, Verschuren MC. In psoriasis lesional skin the type I interferon signaling pathway is activated, whereas interferon-alpha sensitivity is unaltered. J Invest Dermatol 2004;122:51–60. [PubMed: 14962089]93. Gilliet M, Conrad C, Geiges M, Cozzio A, Thurlimann W, Burg G, et al. Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors.Arch Dermatol 2004;140:1490–5. [PubMed: 15611427]94. Theofilopoulos AN, Baccala R, Beutler B, Kono DH. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol 2005;23:307–36. [PubMed: 15771573]95. Fry L. Psoriasis. Br J Dermatol 1988;119:445–61. [PubMed: 3056491]
96. Baker BS, Laman JD, Powles A, van der Fits L, Voerman JS, Melief MJ, et al. Peptidoglycan and
peptidoglycan-specific Th1 cells in psoriatic skin lesions. J Pathol 2006;209:174–81. [PubMed:16493599]
97. Johnston A, Gudjonsson JE, Sigmundsdottir H, Love TJ, Valdimarsson H. Peripheral blood T cell
responses to keratin peptides that share sequences with streptococcal M proteins are largely restricted to skin-homing CD8(+) T cells. Clin Exp Immunol 2004;138:83–93. [PubMed: 15373909]
98. McFadden JP, Baker BS, Powles AV, Fry L. Psoriasis and streptococci: the natural selection of
psoriasis revisited. Br J Dermatol 2009;160:929–37. [PubMed: 19309365]
99. Pias EK, Hilario-Vargas J, Li N, Diaz LA. Humoral autoimmunity in pemphigus. Autoimmunity
2004;37:283–6. [PubMed: 15518042]
100. Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, et al. Plasmacytoid dendritic
cells sense self-DNA coupled with antimicrobial peptide. Nature 2007;449:564–9. [PubMed:17873860]
NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript
Figure 1.Potential of HLA-Cw6 to regulate adaptive as well as innate immune responses. HLA-Cw6expressed on antigen presenting cells (APCs) such as dendritic cells can trigger adaptive
immune responses via presentation of processed antigen to the TCR of CD8+ T cells. In
addition, innate immune response can be elicited by interaction of HLA-Cw6 with its natural Killer immunoglobulin-like receptors expressed on NK and NKT cells.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Figure 2.Role of CD4 T cell subtypes in psoriasis. Pro-inflammatory cytokines produced from Th1 and Th17 dominate the cytokine profile in psoriasis. They mediate keratinocyte hyperproliferation and trigger a ‘vicious cycle’ of inflammation. IL-23 released by psoriatic keratinocytes and
sentinel cells such as dendritic cells and macrophages, is critical for maintenance of Th17function. Low levels of anti-inflammatory cytokines released by Th2 and Treg cells potentially counteract but cannot balance the effects of Th1/Th17 cytokines. Green arrows denote stimulatory actions, red blocking lines denote inhibitory actions.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Figure 3.Immune cell types and interactions implicated in psoriasis. Green dot denotes Th1 cytokines including IFNg and TNFa. Purple dot denotes cytokines produced by Th17 including IL17A,
IL17F and IL22. Red dot denotes other inflammatory mediators such as IL-2 and IL-6. Low levels of anti-inflammatory cytokines released by Th2 and Treg cells potentially counteract but cannot balance the effects of Th1/Th17 cytokines. Th1 and Th2 cells have a mutually inhibitory effect as denoted by the red line. Treg inhibits Th1 actions as denoted by the red arrow.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
The way 的用法 Ⅰ常见用法： 1)the way+ that 2)the way + in which（最为正式的用法） 3)the way + 省略（最为自然的用法） 举例：I like the way in which he talks. I like the way that he talks. I like the way he talks. Ⅱ习惯用法： 在当代美国英语中，the way用作为副词的对格，“the way+ 从句”实际上相当于一个状语从句来修饰整个句子。 1)The way =as I am talking to you just the way I’d talk to my own child. He did not do it the way his friends did. Most fruits are naturally sweet and we can eat them just the way they are—all we have to do is to clean and peel them. 2）The way= according to the way/ judging from the way The way you answer the question, you are an excellent student. The way most people look at you, you’d think trash man is a monster. 3）The way =how/ how much No one can imagine the way he missed her. 4）The way =because
The way的用法及其含义（二） 二、the way在句中的语法作用 the way在句中可以作主语、宾语或表语： 1.作主语 The way you are doing it is completely crazy.你这个干法简直发疯。 The way she puts on that accent really irritates me. 她故意操那种口音的样子实在令我恼火。The way she behaved towards him was utterly ruthless. 她对待他真是无情至极。 Words are important, but the way a person stands, folds his or her arms or moves his or her hands can also give us information about his or her feelings. 言语固然重要,但人的站姿,抱臂的方式和手势也回告诉我们他(她)的情感。 2.作宾语 I hate the way she stared at me.我讨厌她盯我看的样子。 We like the way that her hair hangs down.我们喜欢她的头发笔直地垂下来。 You could tell she was foreign by the way she was dressed. 从她的穿著就可以看出她是外国人。 She could not hide her amusement at the way he was dancing. 她见他跳舞的姿势，忍俊不禁。 3.作表语 This is the way the accident happened.这就是事故如何发生的。 Believe it or not, that's the way it is. 信不信由你, 反正事情就是这样。 That's the way I look at it, too. 我也是这么想。 That was the way minority nationalities were treated in old China. 那就是少数民族在旧中
定冠词the的用法： 定冠词the与指示代词this ,that同源,有“那(这)个”的意思,但较弱,可以和一个名词连用,来表示某个或某些特定的人或东西. (1)特指双方都明白的人或物 Take the medicine.把药吃了. (2)上文提到过的人或事 He bought a house.他买了幢房子. I've been to the house.我去过那幢房子. (3)指世界上独一无二的事物 the sun ,the sky ,the moon, the earth (4)单数名词连用表示一类事物 the dollar 美元 the fox 狐狸 或与形容词或分词连用,表示一类人 the rich 富人 the living 生者 (5)用在序数词和形容词最高级,及形容词等前面 Where do you live?你住在哪? I live on the second floor.我住在二楼. That's the very thing I've been looking for.那正是我要找的东西. (6)与复数名词连用,指整个群体 They are the teachers of this school.(指全体教师) They are teachers of this school.(指部分教师) (7)表示所有,相当于物主代词,用在表示身体部位的名词前 She caught me by the arm.她抓住了我的手臂. (8)用在某些有普通名词构成的国家名称,机关团体,阶级等专有名词前 the People's Republic of China 中华人民共和国 the United States 美国 (9)用在表示乐器的名词前 She plays the piano.她会弹钢琴. (10)用在姓氏的复数名词之前,表示一家人 the Greens 格林一家人(或格林夫妇) (11)用在惯用语中 in the day, in the morning... the day before yesterday, the next morning... in the sky... in the dark... in the end... on the whole, by the way...
“tｈｅwａｙ+从句”结构的意义及用法 首先让我们来看下面这个句子: Ｒead the foｌloｗｉnｇpassagｅａnd talkａbout ｉt wi ｔh your classmaｔes．Try tｏｔeｌl whaｔyｏu thiｎk ｏf Tom aｎd ｏｆｔhe ｗay the chiｌｄrenｔrｅated ｈim. 在这个句子中，ｔhe waｙ是先行词,后面是省略了关系副词that或in whｉch的定语从句。 下面我们将叙述“the ｗaｙ+从句”结构的用法。 1.tｈe wａy之后，引导定语从句的关系词是tｈat而不是hoｗ,因此，<<现代英语惯用法词典＞＞中所给出的下面两个句子是错误的：Ｔhｉs is ｔｈeｗayｈowｉtｈａppened. This is the way how he ａlwａｙs treats me. 2．在正式语体中,thaｔ可被in which所代替;在非正式语体中，ｔhat则往往省略。由此我们得到theｗay后接定语从句时的三种模式：1) tｈe ｗaｙ＋ｔhａt-从句２）the way +ｉn whiｃh－从句3) the ｗay +从句 例如：Ｔｈe way(in whiｃh ，thａt) ｔhｅｓｅｃomｒade ｓloｏｋａｔｐrobｌems is wrong．这些同志看问题的方法
不对。 Ｔｈｅｗａy(that ,ｉn ｗhiｃh)yoｕ’ｒe doinｇit is comple ｔeｌy crａzy.你这么个干法,简直发疯。 Wｅａdmiｒｅd him for thｅｗay ｉｎｗhｉch he fａｃeｓdiｆficultieｓ． Waｌlａｃe ａｎd Ｄarwiｎｇreed ｏn the way ｉｎwhi ｃh ｄｉfｆｅrｅnt forms ｏf life had ｂegｕn.华莱士和达尔文对不同类型的生物是如何起源的持相同的观点。 Thｉs is ｔｈe ｗaｙ（tｈａｔ) hｅdｉd it. I lｉkeｄｔhe waｙ(ｔhat) ｓｈeｏｒganized ｔhe ｍeetｉng． 3.theｗay(tｈat)有时可以与hｏw(作“如何”解）通用。例如： That’s tｈe ｗaｙ(tｈaｔ) shｅspoke. = Tｈat’s how shｅspoke.
表示“方式”、“方法”，注意以下用法： 1.表示用某种方法或按某种方式，通常用介词in(此介词有时可省略)。如： Do it (in) your own way. 按你自己的方法做吧。 Please do not talk (in) that way. 请不要那样说。 2.表示做某事的方式或方法，其后可接不定式或of doing sth。 如： It’s the best way of studying [to study] English. 这是学习英语的最好方法。 There are different ways to do [of doing] it. 做这事有不同的办法。 3.其后通常可直接跟一个定语从句(不用任何引导词)，也可跟由that 或in which 引导的定语从句，但是其后的从句不能由how 来引导。如： 我不喜欢他说话的态度。 正：I don’t like the way he spoke. 正：I don’t like the way that he spoke. 正：I don’t like the way in which he spoke. 误：I don’t like the way how he spoke. 4.注意以下各句the way 的用法： That’s the way (=how) he spoke. 那就是他说话的方式。 Nobody else loves you the way(=as) I do. 没有人像我这样爱你。 The way (=According as) you are studying now, you won’tmake much progress. 根据你现在学习情况来看，你不会有多大的进步。 2007年陕西省高考英语中有这样一道单项填空题： ——I think he is taking an active part insocial work. ——I agree with you_____. A、in a way B、on the way C、by the way D、in the way 此题答案选A。要想弄清为什么选A，而不选其他几项，则要弄清选项中含way的四个短语的不同意义和用法，下面我们就对此作一归纳和小结。 一、in a way的用法 表示：在一定程度上，从某方面说。如： In a way he was right.在某种程度上他是对的。注：in a way也可说成in one way。 二、on the way的用法 1、表示：即将来(去)，就要来(去)。如： Spring is on the way.春天快到了。 I'd better be on my way soon.我最好还是快点儿走。 Radio forecasts said a sixth-grade wind was on the way.无线电预报说将有六级大风。 2、表示：在路上，在行进中。如： He stopped for breakfast on the way.他中途停下吃早点。 We had some good laughs on the way.我们在路上好好笑了一阵子。 3、表示：(婴儿)尚未出生。如： She has two children with another one on the way.她有两个孩子，现在还怀着一个。 She's got five children，and another one is on the way.她已经有5个孩子了，另一个又快生了。 三、by the way的用法
The way的用法及其含义（一） 有这样一个句子：In 1770 the room was completed the way she wanted. 1770年，这间琥珀屋按照她的要求完成了。 the way在句中的语法作用是什么？其意义如何？在阅读时，学生经常会碰到一些含有the way 的句子，如：No one knows the way he invented the machine. He did not do the experiment the way his teacher told him.等等。他们对the way 的用法和含义比较模糊。在这几个句子中，the way之后的部分都是定语从句。第一句的意思是，“没人知道他是怎样发明这台机器的。”the way的意思相当于how；第二句的意思是，“他没有按照老师说的那样做实验。”the way 的意思相当于as。在In 1770 the room was completed the way she wanted.这句话中，the way也是as的含义。随着现代英语的发展，the way的用法已越来越普遍了。下面，我们从the way的语法作用和意义等方面做一考查和分析： 一、the way作先行词，后接定语从句 以下3种表达都是正确的。例如：“我喜欢她笑的样子。” 1. the way+ in which +从句 I like the way in which she smiles. 2. the way+ that +从句 I like the way that she smiles. 3. the way + 从句(省略了in which或that) I like the way she smiles. 又如：“火灾如何发生的，有好几种说法。” 1. There were several theories about the way in which the fire started. 2. There were several theories about the way that the fire started.
way 的用法 【语境展示】 1. Now I’ll show you how to do the experiment in a different way. 下面我来演示如何用一种不同的方法做这个实验。 2. The teacher had a strange way to make his classes lively and interesting. 这位老师有种奇怪的办法让他的课生动有趣。 3. Can you tell me the best way of working out this problem? 你能告诉我算出这道题的最好方法吗？ 4. I don’t know the way (that / in which) he helped her out. 我不知道他用什么方法帮助她摆脱困境的。 5. The way (that / which) he talked about to solve the problem was difficult to understand. 他所谈到的解决这个问题的方法难以理解。 6. I don’t like the way that / which is being widely used for saving water. 我不喜欢这种正在被广泛使用的节水方法。 7. They did not do it the way we do now. 他们以前的做法和我们现在不一样。 【归纳总结】 ●way作“方法，方式”讲时，如表示“以……方式”，前面常加介词in。如例1； ●way作“方法，方式”讲时，其后可接不定式to do sth.，也可接of doing sth. 作定语，表示做某事的方法。如例2，例3；
t h e-w a y-的用法
The way 的用法 "the way+从句"结构在英语教科书中出现的频率较高, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或 in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 一.在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮.
way的用法总结大全 way的用法你知道多少，今天给大家带来way的用法，希望能够帮助到大家，下面就和大家分享，来欣赏一下吧。 way的用法总结大全 way的意思 n. 道路,方法,方向,某方面 adv. 远远地，大大地 way用法 way可以用作名词 way的基本意思是“路,道,街,径”,一般用来指具体的“路,道路”,也可指通向某地的“方向”“路线”或做某事所采用的手段,即“方式,方法”。way还可指“习俗,作风”“距离”“附近,周围”“某方面”等。 way作“方法,方式,手段”解时,前面常加介词in。如果way前有this, that等限定词,介词可省略,但如果放在句首,介词则不可省略。
way作“方式,方法”解时,其后可接of v -ing或to- v 作定语,也可接定语从句,引导从句的关系代词或关系副词常可省略。 way用作名词的用法例句 I am on my way to the grocery store.我正在去杂货店的路上。 We lost the way in the dark.我们在黑夜中迷路了。 He asked me the way to London.他问我去伦敦的路。 way可以用作副词 way用作副词时意思是“远远地,大大地”,通常指在程度或距离上有一定的差距。 way back表示“很久以前”。 way用作副词的用法例句 It seems like Im always way too busy with work.我工作总是太忙了。 His ideas were way ahead of his time.他的思想远远超越了他那个时代。 She finished the race way ahead of the other runners.她第一个跑到终点,远远领先于其他选手。 way用法例句
t h e_w a y的用法大全
The way 在the way+从句中, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或 in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 如果怕弄混淆，下面的可以不看了 另外，在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮. the way=according to the way/judging from the way 4)The way you answer the qquestions, you must be an excellent student. 从你回答就知道,你是一个优秀的学生. 5)The way most people look at you, you'd think a trashman was a monster. 从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物. the way=how/how much 6)I know where you are from by the way you pronounce my name. 从你叫我名字的音调中,我知道你哪里人. 7)No one can imaine the way he misses her. 人们很想想象他是多么想念她. the way=because 8) No wonder that girls looks down upon me, the way you encourage her. 难怪那姑娘看不起我, 原来是你怂恿的
The way 的用法 "the way+从句"结构在英语教科书中出现的频率较高, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 一.在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮.
the way=according to the way/judging from the way 4)The way you answer the qquestions, you must be an excellent student. 从你回答就知道,你是一个优秀的学生. 5)The way most people look at you, you'd think a trashman was a monster. 从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物. the way=how/how much 6)I know where you are from by the way you pronounce my name. 从你叫我名字的音调中,我知道你哪里人. 7)No one can imaine the way he misses her. 人们很想想象他是多么想念她. the way=because 8) No wonder that girls looks down upon me, the way you encourage her. 难怪那姑娘看不起我, 原来是你怂恿的 the way =while/when(表示对比) 9)From that day on, they walked into the classroom carrying defeat on their shoulders the way other students carried textbooks under their arms. 从那天起,其他同学是夹着书本来上课,而他们却带着"失败"的思想负担来上课.
The way的用法及其含义（三） 三、the way的语义 1. the way=as（像） Please do it the way I’ve told you.请按照我告诉你的那样做。 I'm talking to you just the way I'd talk to a boy of my own.我和你说话就像和自己孩子说话一样。 Plant need water the way they need sun light. 植物需要水就像它们需要阳光一样。 2. the way=how（怎样，多么） No one can imagine the way he misses her.没人能够想象出他是多么想念她！ I want to find out the way a volcano has formed.我想弄清楚火山是怎样形成的。 He was filled with anger at the way he had been treated.他因遭受如此待遇而怒火满腔。That’s the way she speaks.她就是那样讲话的。 3. the way=according as （根据） The way you answer the questions, you must be an excellent student.从你回答问题来看，你一定是名优秀的学生。 The way most people look at you, you'd think a trash man was a monster.从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物。 The way I look at it, it’s not what you do that matters so much.依我看，重要的并不是你做什么。 I might have been his son the way he talked.根据他说话的样子，好像我是他的儿子一样。One would think these men owned the earth the way they behave.他们这样行动，人家竟会以为他们是地球的主人。
一．Way：“方式”、“方法” 1.表示用某种方法或按某种方式 Do it (in) your own way. Please do not talk (in) that way. 2.表示做某事的方式或方法 It’s the best way of studying [to study] English.。 There are different ways to do [of doing] it. 3.其后通常可直接跟一个定语从句(不用任何引导词)，也可跟由that 或in which 引导的定语从句 正：I don’t like the way he spoke. I don’t like the way that he spoke. I don’t like the way in which he spoke.误：I don’t like the way how he spoke. 4. the way 的从句 That’s the way (=how) he spoke. I know where you are from by the way you pronounce my name. That was the way minority nationalities were treated in old China. Nobody else loves you the way(=as) I do. He did not do it the way his friend did. 二．固定搭配 1. In a/one way：In a way he was right. 2. In the way /get in one’s way I'm afraid your car is in the way， If you are not going to help，at least don't get in the way. You'll have to move－you're in my way. 3. in no way Theory can in no way be separated from practice. 4. On the way (to……) Let’s wait a few moments. He is on the way Spring is on the way. Radio forecasts said a sixth-grade wind was on the way. She has two children with another one on the way. 5. By the way By the way，do you know where Mary lives? 6. By way of Learn English by way of watching US TV series. 8. under way 1. Elbow one’s way He elbowed his way to the front of the queue. 2. shoulder one’s way 3. feel one‘s way 摸索着向前走；We couldn’t see anything in the cave, so we had to feel our way out 4. fight/force one’s way 突破。。。而前进The surrounded soldiers fought their way out. 5.. push/thrust one‘s way（在人群中）挤出一条路He pushed his way through the crowd. 6. wind one’s way 蜿蜒前进 7. lead the way 带路，领路；示范 8. lose one‘s way 迷失方向 9. clear the way 排除障碍，开路迷路 10. make one’s way 前进，行进The team slowly made their way through the jungle.
在the way+从句中, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 如果怕弄混淆，下面的可以不看了 另外，在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮. the way=according to the way/judging from the way 4)The way you answer the qquestions, you must be an excellent student. 从你回答就知道,你是一个优秀的学生. 5)The way most people look at you, you'd think a trashman was a monster. 从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物. the way=how/how much 6)I know where you are from by the way you pronounce my name. 从你叫我名字的音调中,我知道你哪里人. 7)No one can imaine the way he misses her. 人们很想想象他是多么想念她. the way=because 8) No wonder that girls looks down upon me, the way you encourage her. 难怪那姑娘看不起我, 原来是你怂恿的 the way =while/when(表示对比) 9)From that day on, they walked into the classroom carrying defeat on their shoulders the way other students carried textbooks under their arms.
“the way+从句”结构的意义及用法 首先让我们来看下面这个句子： Read the following passage and talk about it with your classmates. Try to tell what you think of Tom and of the way the children treated him. 在这个句子中，the way是先行词，后面是省略了关系副词that 或in which的定语从句。 下面我们将叙述“the way+从句”结构的用法。 1．the way之后，引导定语从句的关系词是that而不是how,因此，<<现代英语惯用法词典>>中所给出的下面两个句子是错误的：This is the way how it happened. This is the way how he always treats me. 2. 在正式语体中，that可被in which所代替；在非正式语体中，that则往往省略。由此我们得到the way后接定语从句时的三种模式：1) the way +that-从句2) the way +in which-从句3) the way +从句 例如：The way(in which ,that) these comrades look at problems is wrong.这些同志看问题的方法不对。
The way(that ,in which)you’re doing it is completely crazy.你这么个干法，简直发疯。 We admired him for the way in which he faces difficulties. Wallace and Darwin greed on the way in which different forms of life had begun.华莱士和达尔文对不同类型的生物是如何起源的持相同的观点。 This is the way (that) he did it. I liked the way (that) she organized the meeting. 3.the way(that)有时可以与how(作“如何”解)通用。例如： That’s the way (that) she spoke. = That’s how she spoke. I should like to know the way/how you learned to master the fundamental technique within so short a time. 4．the way的其它用法：以上我们讲的都是用作先行词的the way，下面我们将叙述它的一些用法。
定冠词the的12种用法 定冠词the 的12 种用法，全知道?快来一起学习吧。下面就和大家分享，来欣赏一下吧。 定冠词the 的12 种用法，全知道? 定冠词the用在各种名词前面，目的是对这个名词做个记号，表示它的特指属性。所以在词汇表中，定冠词the 的词义是“这个，那个，这些，那些”，可见，the 即可以放在可数名词前，也可以修饰不可数名词，the 后面的名词可以是单数，也可以是复数。 定冠词的基本用法： (1) 表示对某人、某物进行特指，所谓的特指就是“不是别的，就是那个!”如： The girl with a red cap is Susan. 戴了个红帽子的女孩是苏珊。 (2) 一旦用到the，表示谈话的俩人都知道说的谁、说的啥。如：
The dog is sick. 狗狗病了。(双方都知道是哪一只狗) (3) 前面提到过的，后文又提到。如： There is a cat in the tree.Thecat is black. 树上有一只猫，猫是黑色的。 (4) 表示世界上唯一的事物。如： The Great Wall is a wonder.万里长城是个奇迹。(5) 方位名词前。如： thenorth of the Yangtze River 长江以北地区 (6) 在序数词和形容词最高级的前面。如： Who is the first?谁第一个? Sam is the tallest.山姆最高。 但是不能认为，最高级前必须加the，如： My best friend. 我最好的朋友。 (7) 在乐器前。如： play the flute 吹笛子
Way用法 A:I think you should phone Jenny and say sorry to her. B:_______. It was her fault. A. No way B. Not possible C. No chance D. Not at all 说明：正确答案是A. No way，意思是“别想！没门！决不！” 我认为你应该打电话给珍妮并向她道歉。 没门！这是她的错。 再看两个关于no way的例句： （1）Give up our tea break? NO way! 让我们放弃喝茶的休息时间？没门儿！ （2）No way will I go on working for that boss. 我决不再给那个老板干了。 way一词含义丰富，由它构成的短语用法也很灵活。为了便于同学们掌握和用好它，现结合实例将其用法归纳如下： 一、way的含义 1. 路线
He asked me the way to London. 他问我去伦敦的路。 We had to pick our way along the muddy track. 我们不得不在泥泞的小道上择路而行。 2. （沿某）方向 Look this way, please. 请往这边看。 Kindly step this way, ladies and gentlemen. 女士们、先生们，请这边走。 Look both ways before crossing the road. 过马路前向两边看一看。 Make sure that the sign is right way up. 一定要把符号的上下弄对。 3. 道、路、街，常用以构成复合词 a highway（公路），a waterway（水路），a railway（铁路），wayside（路边）
way/time的特殊用法 1、当先行词是way意思为”方式.方法”的时候,引导定语从句的关系词有下列3种形式： Way在从句中做宾语 The way that / which he explained to us is quite simple. Way在从句中做状语 The way t hat /in which he explained the sentence to us is quite simple. 2、当先行词是time时,若time表示次数时,应用关系代词that引导定语从句,that可以省略; 若time表示”一段时间”讲时,应用关系副词when或介词at/during + which引导定语从句 1.Is this factory _______ we visited last year? 2.Is this the factory-------we visited last year? A. where B in which C the one D which 3. This is the last time _________ I shall give you a lesson. A. when B that C which D in which 4.I don’t like the way ________ you laugh at her. A . that B on which C which D as 5.He didn’t understand the wa y ________ I worked out the problem. A which B in which C where D what 6.I could hardly remember how many times----I’ve failed. A that B which C in which D when 7.This is the second time--------the president has visited the country. A which B where C that D in which 8.This was at a time------there were no televisions, no computers or radios. A what B when C which D that