key: cord-0850588-nru3tfh1
authors: Huang, Yi-Wei; Tsai, Tsen-Fang
title: HLA-Cw1 and Psoriasis
date: 2021-01-18
journal: Am J Clin Dermatol
DOI: 10.1007/s40257-020-00585-1
sha: 0fdf4d7fab3096c2d33cd3a734bc0134707db175
doc_id: 850588
cord_uid: nru3tfh1

Psoriasis is a chronic inflammatory skin condition with regional and ethnic differences in its prevalence and clinical manifestations. Human leukocyte antigen (HLA)-Cw6 is the disease allele conferring the greatest risk to psoriasis, but its prevalence is lower in Asian individuals. Recent studies have found associations between HLA-Cw1 and some Asian populations with psoriasis, especially Southern Chinese. HLA-Cw6 was associated with type I early-onset psoriasis, guttate psoriasis, Koebner phenomenon, and better response to methotrexate, interleukin (IL)-12/23, IL-17, and IL-23 targeting drugs. In contrast, HLA-Cw1 positivity has been associated with erythrodermic psoriasis, pustular psoriasis, and the axial type of psoriatic arthritis. Furthermore, HLA-Cw1 was more frequently associated with high-need patients who did not respond to conventional therapies. No known trigger factor nor autoantigen has been identified for HLA-Cw1 positivity. However, HLA-Cw1 has been linked to some viral agents. For example, cytotoxic T lymphocytes recognize multiple cytomegalovirus pp65-derived epitopes presented by HLA alleles, including HLA-C*01:02. In addition, cytomegalovirus can lead to severe exacerbation of psoriatic skin disease. The proposed interaction between viral infection, HLA-Cw1, and psoriasis is through the killer cell immunoglobulin-like receptors of natural killer cells. Given the diverse nature of psoriasis pathogenesis and the difference in HLA-Cw prevalence in different racial groups, more studies are needed to confirm the role of HLA-Cw1 in psoriasis.

Psoriasis is a common inflammatory disease characterized by the infiltration of inflammatory cells into the epidermis and altered keratinocyte differentiation. Genes, immune dysregulations, and environmental triggers are the three critical factors in its pathogenesis. However, psoriasis is a heterogeneous disease presenting with different manifestations. Its prevalence varies from 0.09 to 5.1% [1] . Genome-wide association studies have identified more than 60 psoriasis susceptibility regions, which are believed to contribute to the activation of T helper-17 cells [2, 3] . In a meta-analysis of genome-wide association studies, 63 loci have been identified for European ancestry individuals [4] . Among all the psoriasis susceptibility genes, human leukocyte antigen (HLA)-C*06:02 is the most significant risk allele. HLA-C is involved in the immune responses by presenting antigens to CD8+ T cells, the main inflammatory T cells that migrate into the epidermis, and by interacting with natural killer (NK) cell receptors [5, 6] . The impact of HLA-Cw6 on psoriasis has been reviewed [7] . However, the prevalence of HLA-C*06:02 varies widely, higher in Caucasian than in Asian individuals [7] . The frequencies of the HLA-Cw6 allele were only 18.6% and 16.18% among Chinese patients with psoriasis [8, 9] , while the prevalence was 45.9% in Finnish patients with psoriasis [10] . The effect of other HLA-Cw alleles on psoriasis is less studied. Recently, HLA-C*01:02 and HLA-A*02:07 were reported to confer a specific risk for psoriatic patients in Southern China [11] . HLA-C*01 has also been identified as a common HLA-C in some other ethnicities [11] [12] [13] [14] [15] [16] [17] .

There are ethnic differences in the presentation of psoriasis. Infection is a less common trigger for psoriasis in Asian individuals [18] . Atopic dermatitis in Chinese patients was shown to have more psoriasiform features [19] . A T helper-2-high psoriasis cluster has also been identified based on gene expression profiles of lesional skin specimens in a Chinese psoriasis population [20] . In specific ethnicities, some distinct characteristics were observed in HLA-Cw1-positive patients [21, 22] . Therefore, it is important to summarize the current reports regarding the role of HLA-Cw*01 in the complex interplay between immunity and psoriasis.

Enhanced wound-healing abilities and a lower risk of infections, in particular leprosy, were reported in patients with psoriasis [23] . The resistance to infections has been partially attributed to the overexpressed antimicrobial peptides. One of which is believed to be LL-37, a cathelicidin peptide that is increased when the skin is exposed to external factors, such as skin trauma or infection [24] . LL-37 has antimicrobial activity and immunomodulatory functions, including induction of immune mediators and regulation of inflammatory responses, linking the antimicrobial defense system with the pathogenesis of psoriasis [24] . In psoriatic skin, LL-37 activates plasmacytoid dendritic cells by forming a complex with self-DNA, initiating interferon-alpha production [25] . Another study simulating the interaction confirmed the high binding affinities of smaller peptides derived from LL-37 to the HLA-C*06:02 molecule [26] . The complex formed by LL-37 serves as an autoantigen, which interacts with a T-cell receptor, leading to the pathogenic T-cell response in psoriasis [26] . In addition, patients with HLA-Cw*06:02 homozygotes showed significantly more improvement in the Psoriasis Area Severity Index, compared with heterozygous and HLA-Cw*06:02-negative patients after a tonsillectomy [27] .

Other proposed autoantigens of psoriasis include a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-like protein 5 [28] , and keratin 17 [29] , a peptide constitutively expressed in hair follicles that shares extensive sequence homology with streptococcal M proteins [30] . Moreover, HLA-C*06:02 has been linked with positive swabs indicating streptococcal throat infections and chronic or recurrent streptococcal tonsillitis [31, 32] . In contrast, HLA-Cw*01:02 represents an HLA-C group 1 (HLA-C1) molecule and interacts with the KIR2DL2 and KIR2DL3 receptors, which normally inhibit the cytotoxicity of NK cells [33] [34] [35] . Briefly, HLA-Cw*01:02-binding peptides antagonize the inhibition mediated by KIR2DL2/KIR2DL3, leading to activation of NK cells [35] . In a meta-analysis of five articles, the KIR2DL2 polymorphism was significantly associated with psoriatic arthritis (odds ratio [OR] = 1.269, p = 0.003) [36] . Theoretically, the differences in HLA-Cw distribution may influence the clinical manifestations and types of trigger factors for psoriatic diseases [18, 37] . However, the immunological function of the HLA-C locus alleles was questioned from an evolutionary aspect [38] , and there is significant linkage disequilibrium within the extended haplotype harboring HLA-Cw, with A*02:07-C*01:02-B*46:01 present in the Southern China population [39, 40] . Thus, further studies are required to investigate the roles of HLA-C*01 and its corresponding antigens/autoantigens in the pathogenesis of psoriasis.

There is evidence supporting the association between HLA-Cw1 and psoriatic diseases in different ethnic groups (Table 1) , especially in Thai [12] and Southern China populations [11] . In Thai patients, the HLA-Cw1 allele frequency of type I early-onset psoriasis compared with controls was 35% vs 16% (p < 0.05) [13] . Type II psoriasis, which was characterized by an age at onset greater than 40 years, also exhibited a higher allele frequency of Cw1 at 29% compared with controls at 16% (p < 0.05) [13] . In a study that compared the HLA susceptibility of 4493 patients with psoriasis and 4649 controls from Southern China, and 3657 patients with psoriasis and 5257 controls from Northern China, HLA-C*06:02 and HLA-C*07:04 were significantly increased in both patient groups. However, HLA-C*01:02 (OR = 1.32, p = 2.45 × 10 -7 ) and HLA-A*02:07 (OR = 1.67, p = 2.49 × 10 -11 ) were associated with an increased risk of psoriasis only in patients from Southern China using a logistic regression and stepwise conditional analysis [11] . HLA-C*06:02 and HLA-C*07:04 showed similarities in peptide binding preference [41] , whereas HLA-C*01 and HLA-A*02 [42] have very similar binding motifs, suggesting possible yet unidentified antigen/autoantigens in the pathogenesis of patients with psoriasis with HLA-Cw1 positivity. Interestingly, HLA-A*02:07 was also reported to be associated with psoriasis in Japanese individuals [43] .

Additionally, the HLA-C*01 allele was significantly more frequent in Turkish patients with psoriasis than in control groups (8.1% vs 2.1%, p = 0.02), leading to an OR of 4.15 (95% confidence interval [CI] 1.15-15.01) [14] . In one study that recruited Kuwait children, the association of HLA-Cw1 with psoriasis was observed in 9 out of 50, resulting in an OR of 3.01 (95% CI 1.00-9.50) [15] . In the same study, among 25 patients with a positive family history, seven patients carried the HLA-Cw1 allele, indicating an OR of 5.44 (95% CI 1.46-19.35) [15] . Another study focusing on the Pakistani population revealed an association between HLA-Cw1 and psoriasis (OR = 1.66) [16] . Significant HLA-C allele associations were observed in Singapore Chinese patients with psoriasis, with an OR of 2.19 (95% CI 1.45-3.33) for HLA-Cw1 [17] . However, no association between HLA-Cw1 and Caucasian patients with psoriasis was observed [12] .

The strong connections between HLA-Cw6 and psoriatic diseases have been well documented [7] . One review article highlighted that the allele is associated with early-onset psoriasis, guttate psoriasis, psoriatic arthritis, and Koebner phenomenon [7] . Patients with psoriatic arthritis with HLA-Cw6 positivity more often have an early onset, and their cutaneous symptoms often develop before arthritis [7] . HLA-Cw6-positive patients have been shown in several studies to be more responsive to methotrexate [44, 45] , anti-interleukin (IL)-12/23 [46, 47] , anti-IL-17 [48, 49] and IL-23 drugs [50] . However, inconsistent data were reported in patients receiving secukinumab [51] . Moreover, anti-tumor necrosis factor agents showed less efficacy in patients with HLA-Cw6-positive psoriasis [48] . In comparison, HLA-Cw1-B46 carriers were reported to be clinically distinct, showing a lower risk of disease, greater nail involvement, and a later age at onset [12] . Interestingly, the HLA-Cw1-B46 haplotype imparts a risk for Asian individuals [12] . Erythrodermic psoriasis is a potentially fatal presentation of psoriasis. A higher frequency of severe psoriasis was reported in Asian individuals, [52] as well as erythrodermic psoriasis (OR = 5.56, p = 0.018) [37] . In Chinese patients with erythrodermic psoriasis, HLA-C*01:02 was reported to be the most frequent HLA-C allele (34.4%). ]21]. Regarding the allele frequencies of individuals carrying HLA-C*01:02, patients with plaque psoriasis (21.9%) had a significantly lower frequency than those with erythrodermic psoriasis (34.4%, p = 0.02), but was similar to healthy controls (21.2%) [21] . HLA-Cw1 phenotype frequency is significantly increased in Japanese patients with generalized pustular psoriasis, standing at 46.2% compared with 22.2% in healthy controls [22] . Based on a study recruiting Thai patients with psoriasis, a significant increase of MICA*010 in patients with psoriasis represents a marker of the HLA-B46-Cw1 haplotype [53] . The severity of psoriasis was also found to be associated with HLA-Cw1 in a Chinese study. The HLA-Cw1 allele was significantly increased in patients with moderate-tosevere psoriasis compared with all patients with psoriasis (32% vs 22%, p = 0.023) [54] . The authors also highlighted the elevated allele positivity of HLA-Cw1-B46 compared with all patients with psoriasis (49% vs 29%, p = 0.004). The HLA-Cw1-B46 allele was associated with early-onset (age <40 years) psoriasis (p = 0.012), but not late-onset psoriasis (p = 0.065) [54] . In the same study, differences in the Psoriasis Area Severity Index 50 response to alefacept at week 12 was significant between HLA-Cw1-positive and HLA-Cw1-negative individuals (0% vs 57%, p = 0.026).

A high prevalence of HLA-Cw1 antigens has been described in spondylarthritis since 1978, [55] [56] [57] [58] and in patients with the spondylitis type of psoriatic arthritis [59] . The HLA-Cw1 allele was increased in Spanish patients with psoriatic arthritis, especially the axial type, although this association may be secondary to the linkage between HLA-B27.5 and HLA-Cw1 [60] . In one study, genotyping was performed in 47 Chinese patients with active peripheral-type psoriatic arthritis despite conventional treatment, HLA-Cw*07:02 was the most frequent allele (29.8%), followed by HLA-C*01 (26.6%) [61] . Shao et al. described four phenotypes with a significant positive association with psoriatic arthritis, including HLA-C*01, *02, *06, and *12, in a meta-analysis of European and Middle Eastern descent [62] .

Genetic variations in HLA may be the result of evolutionary adaptation in response to environmental stress, such as climate and the prevalence of infectious diseases [63] . HLA-C plays an essential role in the protection against cancers and viruses, and has also been implicated in rheumatic diseases, including psoriasis and psoriatic arthritis [64] . The HLA serotype may also play a role in the global coronavirus pandemic. In a recent Italian study, HLA-B*44 and HLA-C*01 were found to be positively and independently associated with COVID-19 with a growth rate of 16% per 1% point increase in HLA-B*44 prevalence and of 19% per 1% point increase in HLA-C*01 prevalence [65] .

The proposed function of HLA-C in autoimmune and inflammatory diseases is to present antigens to T cells and to drive the innate immunity through binding activating or inhibitory receptors on NK cells [64] . HLA-Cw1 was increased in patients with various clinical forms of tuberculosis, [66] . which is possibly due to the inhibition of NK cell activity through killer cell immunoglobulinlike receptors [35] . However, a meta-analysis of casecontrol studies failed to confirm this association [67] . Among the HLA-Cw homozygous subjects in a Han cohort seropositive with human immunodeficiency virus type 1, HLA-Cw*01:02 was the predominant allele [68] . HLA-Cw*01:02-presented human immunodeficiency virus type 1 p24 peptide modulates the inhibitory receptor KIR2DL2, leading to functional inhibition of NK cells [6, 69] . Increased risks for tuberculosis onset as well as inflammatory reconstitution inflammatory syndrome were reported to be associated with the KIR2DS2 gene, [70] . demonstrating the participation of HLA-C1 in the activation of NK cells [71] .

The relationship between viral infection, psoriasis, and HLA is complicated. Human immunodeficiency virus infection increased the incidence of psoriasis in different reports [72] [73] [74] . Gambardella et al. [75] reported a patient presenting with cytomegalovirus (CMV), followed by a severe aggravation of psoriasis. Serology investigations of the patient revealed persistent positive IgM anti-CMV > 28 UA/mL, positive IgG anti-CMV, yet negative results for CMV-polymerase chain reaction and IgG anti-CMV avidity [75] . An interactive relationship between the severity of psoriasis and CMV infection has been proposed [76] . To be more specific, reduced circulating CMV-specific T cells were observed in patients with CMV-seropositive psoriasis who received effective anti-psoriatic treatment compared to CMV-positive healthy controls [76] . Cytotoxic T lymphocytes recognize multiple CMV pp65-derived epitopes presented by HLA alleles, including HLA-C*01:02 [77] . In an analysis based on each allotype in the HLA-C locus, the frequency of CMV pp65-specific CD8+ T cells secreting interferon-γ was the highest for HLA-C*08:01, followed by HLA-C*01:02 [78] .

Further evidence supporting the involvement of infectious agents in the pathogenesis of psoriasis through killer cell immunoglobulin-like receptors and NK cells lies in the treatment of psoriasis. In parallel to anti-psoriatic therapy, an enhanced proportion of acute activated CD8+ T cells were replaced by effector differentiated CD8+ T cells in CMV-seropositive patients with severe psoriasis [76] . In contrast to LL-37, a proposed autoantigen for HLA-Cw6, [26] there is no confirmed T-cell autoantigen for HLA-Cw1 to our knowledge. The absence of obvious triggering antigens and the presence of highly prevalent (95%) CMV infection among patients with psoriasis [79] might explain the persistent of more refractory disease activity in patients with HLA-Cw1 positivity. More research is needed to elucidate whether HLA-Cw1 plays a role in triggering or influencing the disease severity of psoriasis.

Psoriasis is linked to systemic inflammation and multiple comorbidities, which is often related to the severity of skin lesions and coexisting psoriatic arthritis [17, 80] . An increased cardiometabolic burden has been highlighted because of the risk of significant morbidities and mortalities. The association of HLA-Cw1 and dyslipidemia was reported in Singapore Chinese patients [17] . Another Japanese cohort demonstrated BTN2A1, a gene within the major histocompatibility complex class I region, may play a role in the higher frequency of dyslipidemia in patients with psoriasis [80] .

In a meta-analysis, patients with psoriasis showed a 2.53-fold risk of developing Crohn's disease and a 1.7-fold risk of developing ulcerative colitis, [81] which could be explained by shared susceptibility loci [82] . The HLA-C*01 allotype has been correlated with an increased risk of Crohn's disease in a large genome-wide association study performed on Korean individuals [83] . In systemic reviews and meta-analyses, patients with psoriasis were also found to have a higher risk of schizophrenia [84] and vice versa [85] . In the Irish Schizophrenia Genomics Consortium, which recruited 1606 patients and 1794 controls, HLA-C*01:02 was identified as the most significant HLA associated with schizophrenia [86] . A shared genetic risk between psoriasis and schizophrenia has been observed [87] .

There is a growing understanding of the immunopathogenesis of immune-mediated inflammatory diseases, such as psoriasis. Involvement of a host gene polymorphism along with the interaction between infectious agents and killer cell immunoglobulin-like receptors of NK cells have been proposed based on investigations of viral infections such as CMV. A summary of characteristics of patients with psoriasis carrying HLA-Cw1 in comparison to HLA-Cw6 is provided in Table 2 . HLA-Cw6 is the most well-recognized HLA serotype, affecting susceptibility, phenotype, disease Kuwait [15] All ethnicities (higher in Caucasians) Pakistan [16] Singapore Chinese [17] Southern Chinese [11] Thai [12] Turkish [14] Phenotypes

Erythrodermic psoriasis [21] Guttate psoriasis Pustular psoriasis [22] Photosensitive Nail involvement [12] Early-onset (type I) Positive family history [15] Psoriatic [81] [82] [83] Atherosclerosis Schizophrenia [84] [85] [86] [87] course, and response to the treatment of psoriasis. Patients with HLA-Cw6 also respond better to conventional treatments and some biologics despite more extensive plaques. HLA-Cw1 is a less recognized but an important HLA-C serotype associated with psoriasis in some Asian ethnicities. Patients carrying HLA-Cw1 tend to show higher disease activity, have an increased risk of developing erythrodermic psoriasis, and are more refractory to treatments. Compared to HLA-Cw6 patients, there is a lack of identified exogenous triggers or autoantigens in HLA-Cw1 patients with psoriasis. Future research is needed to elucidate the role of HLA-Cw1 in psoriasis.

Funding No funding was received for the preparation of this article.

Yi-Wei Huang has no conflicts of interest that are directly relevant to the content of this article. Tsen-Fang Tsai has conducted clinical trials or received honoraria for serving as a consultant for Abbvie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galderma, Janssen-Cilag, Merck Sharp & Dohme, Novartis International AG, Pfizer Inc., and UCB Pharma.

Ethics Approval Not applicable.

Code Availability Not applicable.

All authors contributed to the study conception and design. The literature search and data analysis were performed by Yi-Wei Huang and Tsen-Fang Tsai. The first draft of the manuscript was written by Yi-Wei Huang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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