Follicular helper- and peripheral helper-like T cells drive autoimmune disease in human immune system mice.

Human immune system (HIS) mice constructed in various ways are widely used for investigations of human immune responses to pathogens, transplants and immunotherapies. In HIS mice that generate T cells de novo from hematopoietic progenitors, T cell-dependent multisystem autoimmune disease occurs, most rapidly when the human T cells develop in the native NOD.Cg- Prkdc scid Il2rg tm1Wjl (NSG) mouse thymus, where negative selection is abnormal. Disease develops very late when human T cells develop in human fetal thymus grafts, where robust negative selection is observed. We demonstrate here that PD-1 + CD4 + peripheral (Tph) helper-like and follicular (Tfh) helper-like T cells developing in HIS mice can induce autoimmune disease. Tfh-like cells were more prominent in HIS mice with a mouse thymus, in which the highest levels of IgG were detected in plasma, compared to those with a human thymus. While circulating IgG and IgM antibodies were autoreactive to multiple mouse antigens, in vivo depletion of B cells and antibodies did not delay the development of autoimmune disease. Conversely, adoptive transfer of enriched Tfh- or Tph-like cells induced disease and autoimmunity-associated B cell phenotypes in recipient mice containing autologous human APCs without T cells. T cells from mice with a human thymus expanded and induced disease more rapidly than those originating in a murine thymus, implicating HLA-restricted T cell-APC interactions in this process. Since Tfh, Tph, autoantibodies and LIP have all been implicated in various forms of human autoimmune disease, the observations here provide a platform for the further dissection of human autoimmune disease mechanisms and therapies.

Inhibition of IL-25/IL-17RA improves immune-related adverse events of checkpoint inhibitors and reveals antitumor activity.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved outcomes and extended patient survival in several tumor types. However, ICIs often induce immune-related adverse events (irAEs) that warrant therapy cessation, thereby limiting the overall effectiveness of this class of therapeutic agents. Currently, available therapies used to treat irAEs might also blunt the antitumor activity of the ICI themselves. Therefore, there is an urgent need to identify treatments that have the potential to be administered alongside ICI to optimize their use. METHODS: Using a translationally relevant murine model of anti-PD-1 and anti-CTLA-4 antibodies-induced irAEs, we compared the safety and efficacy of prednisolone, anti-IL-6, anti-TNFɑ, anti-IL-25 (IL-17E), and anti-IL-17RA (the receptor for IL-25) administration to prevent irAEs and to reduce tumor size. RESULTS: While all interventions were adequate to inhibit the onset of irAEs pneumonitis and hepatitis, treatment with anti-IL-25 or anti-IL-17RA antibodies also exerted additional antitumor activity. Mechanistically, IL-25/IL-17RA blockade reduced the number of organ-infiltrating lymphocytes. CONCLUSION: These findings suggest that IL-25/IL-17RA may serve as an additional target when treating ICI-responsive tumors, allowing for better tumor control while suppressing immune-related toxicities.

PD-1 signaling uncovers a pathogenic subset of T cells in inflammatory arthritis.

BACKGROUND: PD-1 is an immune checkpoint on T cells, and interventions to block this receptor result in T cell activation and enhanced immune response to tumors and pathogens. Reciprocally, despite a decade of research, approaches to treat autoimmunity with PD-1 agonists have only had limited successful. To resolve this, new methods must be developed to augment PD-1 function beyond engaging the receptor. METHODS: We conducted a flow cytometry analysis of T cells isolated from the peripheral blood and synovial fluid of patients with rheumatoid arthritis. In addition, we performed a genome-wide CRISPR/Cas9 screen to identify genes associated with PD-1 signaling. We further analyzed genes involved in PD-1 signaling using publicly available bulk and single-cell RNA sequencing datasets. RESULTS: Our screen confirmed known regulators in proximal PD-1 signaling and, importantly, identified an additional 1112 unique genes related to PD-1 ability to inhibit T cell functions. These genes were strongly associated with the response of cancer patients to PD-1 blockades and with high tumor immune dysfunction and exclusion scores, confirming their role downstream of PD-1. Functional annotation revealed that the most significant genes uncovered were those associated with known immune regulation processes. Remarkably, these genes were considerably downregulated in T cells isolated from patients with inflammatory arthritis, supporting their overall inhibitory functions. A study of rheumatoid arthritis single-cell RNA sequencing data demonstrated that five genes, KLRG1, CRTAM, SLAMF7, PTPN2, and KLRD1, were downregulated in activated and effector T cells isolated from synovial fluids. Backgating these genes to canonical cytotoxic T cell signatures revealed PD-1+ HLA-DRHIGH KLRG1LOW T cells as a novel inflammatory subset of T cells. CONCLUSIONS: We concluded that PD-1+ HLA-DRHIGH KLRG1LOW T cells are a potential target for future PD-1 agonists to treat inflammatory diseases. Our study uncovers new genes associated with PD-1 downstream functions and, therefore, provides a comprehensive resource for additional studies that are much needed to characterize the role of PD-1 in the synovial subset of T cells.

PD-1 signaling uncovers a pathogenic subset of T cells in inflammatory arthritis.

Background: PD-1 is an immune checkpoint on T cells and interventions to block this receptor result in T cell activation and enhanced immune response to tumors. Paired to that, and despite a decade of research, approaches to treat autoimmunity with PD-1 agonists still need to be more successful. To resolve this, new methods must be developed to augment PD-1 function beyond engaging the receptor. Methods: We conducted a flow cytometry analysis of T cells isolated from the peripheral blood and synovial fluid of patients with rheumatoid arthritis. In addition, we performed a genome-wide CRISPR/Cas9 screen to identify genes associated with PD-1 signaling. We further analyzed genes involved in PD-1 signaling using publicly available bulk and single-cell RNA sequencing datasets. Results: Our screen confirmed known regulators in proximal PD-1 signaling and, importantly, found an additional 1,112 unique genes related to PD-1 ability to inhibit T cell functions. These genes were strongly associated with the response of cancer patients to PD-1 blockades and with high tumor immune dysfunction and exclusion scores, confirming their role downstream of PD-1. Functional annotation revealed that more significant genes uncovered were those associated with known immune regulation processes. Remarkably, these genes were considerably downregulated in T cells isolated from patients with inflammatory arthritis, supporting their overall inhibitory functions. A study of rheumatoid arthritis single-cell RNA sequencing data demonstrated that five genes, KLRG1, CRTAM, SLAMF7, PTPN2, and KLRD1, were downregulated in activated and effector T cells isolated from synovial fluids. Back-gating these genes to canonical cytotoxic T cell signatures revealed PD-1 + HLA-DR HIGH KLRG LOW T cells as a novel inflammatory subset of T cells. Conclusion: We concluded that PD-1 + HLA-DR HIGH KLRG LOW T cells are a potential target for future PD-1 agonists to treat inflammatory diseases. Our study uncovers new genes associated with PD-1 downstream functions and, therefore, provides a comprehensive resource for additional studies that are much needed to characterize the role of PD-1 in the synovial subset of T cells.

Single-cell RNA sequencing reveals distinct T cell populations in immune-related adverse events of checkpoint inhibitors.

PD-1 is an inhibitory receptor in T cells, and antibodies that block its interaction with ligands augment anti-tumor immune responses. The clinical potential of these agents is limited by the fact that half of all patients develop immune-related adverse events (irAEs). To generate insights into the cellular changes that occur during anti-PD-1 treatment, we performed single-cell RNA sequencing of circulating T cells collected from patients with cancer. Using the K-nearest-neighbor-based network graph-drawing layout, we show the involvement of distinctive genes and subpopulations of T cells. We identify that at baseline, patients with arthritis have fewer CD8 TCM cells, patients with pneumonitis have more CD4 TH2 cells, and patients with thyroiditis have more CD4 TH17 cells when compared with patients who do not develop irAEs. These data support the hypothesis that different populations of T cells are associated with different irAEs and that characterization of these cells' pre-treatment has the potential to serve as a toxicity-specific predictive biomarker.

Upregulation of type 1 conventional dendritic cells implicates antigen cross-presentation in multisystem inflammatory syndrome.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is an acute, febrile, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated syndrome, often with cardiohemodynamic dysfunction. Insight into mechanism of disease is still incomplete. OBJECTIVE: Our objective was to analyze immunologic features of MIS-C patients compared to febrile controls (FC). METHODS: MIS-C patients were defined by narrow criteria, including having evidence of cardiohemodynamic involvement and no macrophage activation syndrome. Samples were collected from 8 completely treatment-naive patients with MIS-C (SARS-CoV-2 serology positive), 3 patients with unclassified MIS-C-like disease (serology negative), 14 FC, and 5 MIS-C recovery (RCV). Three healthy controls (HCs) were used for comparisons of normal range. Using spectral flow cytometry, we assessed 36 parameters in antigen-presenting cells (APCs) and 29 in T cells. We used biaxial analysis and uniform manifold approximation and projection (UMAP). RESULTS: Significant elevations in cytokines including CXCL9, M-CSF, and IL-27 were found in MIS-C compared to FC. Classic monocytes and type 2 dendritic cells (DCs) were downregulated (decreased CD86, HLA-DR) versus HCs; however, type 1 DCs (CD11c+CD141+CLEC9A+) were highly activated in MIS-C patients versus FC, expressing higher levels of CD86, CD275, and atypical conventional DC markers such as CD64, CD115, and CX3CR1. CD169 and CD38 were upregulated in multiple monocyte subtypes. CD56dim/CD57-/KLRGhi/CD161+/CD38- natural killer (NK) cells were a unique subset in MIS-C versus FC without macrophage activation syndrome. CONCLUSION: Orchestrated by complex cytokine signaling, type 1 DC activation and NK dysregulation are key features in the pathophysiology of MIS-C. NK cell findings may suggest a relationship with macrophage activation syndrome, while type 1 DC upregulation implies a role for antigen cross-presentation.

Role of the thymus in spontaneous development of a multi-organ autoimmune disease in human immune system mice.

We evaluated the role of the thymus in development of multi-organ autoimmunity in human immune system (HIS) mice. T cells were essential for disease development and the same T cell clones with varying phenotypes infiltrated multiple tissues. De novo-generated hematopoietic stem cell (HSC)-derived T cells were the major disease drivers, though thymocytes pre-existing in grafted human thymi contributed if not first depleted. HIS mice with a native mouse thymus developed disease earlier than thymectomized mice with a thymocyte-depleted human thymus graft. Defective structure in the native mouse thymus was associated with impaired negative selection of thymocytes expressing a transgenic TCR recognizing a self-antigen. Disease developed without direct recognition of antigens on recipient mouse MHC. While human thymus grafts had normal structure and negative selection, failure to tolerize human T cells recognizing mouse antigens presented on HLA molecules may explain eventual disease development. These new insights have implications for human autoimmunity and suggest methods of avoiding autoimmunity in next-generation HIS mice.

MHC class I associations beyond HLA-B27: the peptide binding hypothesis of psoriatic arthritis and its implications for disease pathogenesis.

PURPOSE OF REVIEW: To provide an overview of the heterogeneous human leucocyte antigen (HLA) associations of psoriatic arthritis, their relationship to particular clinical features of the disease, and how a hypothesis of binding specific peptides could provide a unifying basis for this heterogeneity. RECENT FINDINGS: There have been substantive advances in understanding the role of HLA molecules in binding self-peptides that select our repertoire of T cells, the specific peptide-binding properties of these HLA allotypes, and their crystallographic structure. These advances provide a means to envision the significance of the heterogeneous psoriatic arthritis HLA associations. The clinical relevance of these allotypes if heightened by emerging knowledge of their relationship to particular clinical features of the disease that serve as subphenotypes. SUMMARY: We propose a peptide binding hypothesis of psoriatic arthritis based on a shared pattern of negative charge in the 'B' pocket of the HLA-B and HLA-C molecules encoded by the susceptibility allotypes. This hypothesis suggests that peptides characterized by the presence of arginine at position 2 or 3 are bound to the susceptibility allotypes and drive the T-cell clones selected on them to attack molecules containing these peptides located in sites of psoriatic arthritis inflammation.

The many faces of psoriatic arthritis: their genetic determinism.

In this review, we propose a model of PsA as a complex genetically determined autoimmune-mediated disease having a heterogeneous variety of subphenotypes, with each subphenotype under the control of a different susceptibility-associated HLA allele. Since the specific HLA molecules encoded by each susceptibility allele dominantly select a T cell repertoire with the property of recognizing different peptides, we hypothesize each subphenotype reflects a distinct adaptive autoimmune response directed to different target molecules that is mediated by T cells within each selected repertoire. The interaction among the patients' susceptibility alleles in the selection of their T cell repertoires determines a spectrum of overall clinical disease severity, varying from mild to severe. We further speculate that these different immune responses may result in activation of different immune effector pathways, which might therefore respond differently to various specific biologic agents.

Correlation of gene expression profiling score, cardiac hemodynamics and echocardiographic parameters in asymptomatic, rejection-free pediatric heart transplant recipients.

OBJECTIVES: To correlate gene expression profiling scores obtained by AlloMap® with cardiac hemodynamics, cardiac allograft vasculopathy (CAV), and echocardiographic parameters in asymptomatic, rejection-free pediatric heart transplant (HT) recipients. METHODS: Single-institution retrospective study of 210 AlloMap scores obtained concomitantly with cardiac catheterization and echocardiogram from 55 children during follow-up after cardiac transplantation. RESULTS: The median age at HT was 5.1 years (range, 0.9-14.1), with 29 males and 26 females. AlloMap scores were high in <2 years vs ≥2 years of age at the time of HT (P = .001), and trending higher with time after HT (R2  = .04, P = .004). There was no significant difference in scores between ACR grades 0 and 1R or CAV. There was mild to modest correlation of AlloMap scores with the mean right atrial pressure (P = .002), and pulmonary capillary wedge pressure (P = .02), but no correlation was found with LV SF% (P = .3), LV EF% (P = .5), or RV FAC % (P = .8). CONCLUSIONS: Our study provides preliminary data that the AlloMap score must be studied carefully before it can be used in children, particularly in those under 2 years of age. Monitoring of serial scores for each patient could potentially reflect changes in allograft performance that may determine indications for catheterization and biopsy which needs to be validated in future studies.

Crossreactive public TCR sequences undergo positive selection in the human thymic repertoire.

We investigated human T-cell repertoire formation using high throughput TCRß CDR3 sequencing in immunodeficient mice receiving human hematopoietic stem cells (HSCs) and human thymus grafts. Replicate humanized mice generated diverse and highly divergent repertoires. Repertoire narrowing and increased CDR3ß sharing was observed during thymocyte selection. While hydrophobicity analysis implicated self-peptides in positive selection of the overall repertoire, positive selection favored shorter shared sequences that had reduced hydrophobicity at positions 6 and 7 of CDR3ßs, suggesting weaker interactions with self-peptides than unshared sequences, possibly allowing escape from negative selection. Sharing was similar between autologous and allogeneic thymi and occurred between different cell subsets. Shared sequences were enriched for allo-crossreactive CDR3ßs and for Type 1 diabetes-associated autoreactive CDR3ßs. Single-cell TCR-sequencing showed increased sharing of CDR3αs compared to CDR3ßs between mice. Our data collectively implicate preferential positive selection for shared human CDR3ßs that are highly cross-reactive. While previous studies suggested a role for recombination bias in producing "public" sequences in mice, our study is the first to demonstrate a role for thymic selection. Our results implicate positive selection for promiscuous TCRß sequences that likely evade negative selection, due to their low affinity for self-ligands, in the abundance of "public" human TCRß sequences.

Quantifying size and diversity of the human T cell alloresponse.

Alloreactive T lymphocytes are the primary mediators of immune responses in transplantation, both in the graft-versus-host and host-versus-graft directions. While essentially all clones comprising the human T cell repertoire have been selected on self-peptide presented by self-human leukocyte antigens (self-HLAs), much remains to be understood about the nature of clones capable of responding to allo-HLA molecules. Quantitative tools to study these cells are critical to understand fundamental features of this important response; however, the large size and diversity of the alloreactive T cell repertoire in humans presents a great technical challenge. We have developed a high-throughput T cell receptor (TCR) sequencing approach to characterize the human alloresponse. We present a statistical method to model T cell clonal frequency distribution and quantify repertoire diversity. Using these approaches, we measured the diversity and frequency of distinct alloreactive CD4+ and CD8+ T cell populations in HLA-mismatched responder-stimulator pairs. Our findings indicate that the alloimmune repertoire is highly specific for a given pair of individuals, that most alloreactive clones circulate at low frequencies, and that a high proportion of TCRs is likely able to recognize alloantigens.

Hypercholesterolemia induces T cell expansion in humanized immune mice.

Emerging data suggest that hypercholesterolemia has stimulatory effects on adaptive immunity and that these effects can promote atherosclerosis and perhaps other inflammatory diseases. However, research in this area has relied primarily on inbred strains of mice whose adaptive immune system can differ substantially from that of humans. Moreover, the genetically induced hypercholesterolemia in these models typically results in plasma cholesterol levels that are much higher than those in most humans. To overcome these obstacles, we studied human immune system-reconstituted mice (hu-mice) rendered hypercholesterolemic by treatment with adeno-associated virus 8-proprotein convertase subtilisin/kexin type 9 (AAV8-PCSK9) and a high-fat/high-cholesterol Western-type diet (WD). These mice had a high percentage of human T cells and moderate hypercholesterolemia. Compared with hu-mice that had lower plasma cholesterol, the PCSK9-WD mice developed a T cell-mediated inflammatory response in the lung and liver. Human CD4+ and CD8+ T cells bearing an effector memory phenotype were significantly elevated in the blood, spleen, and lungs of PCSK9-WD hu-mice, whereas splenic and circulating regulatory T cells were reduced. These data show that moderately high plasma cholesterol can disrupt human T cell homeostasis in vivo. This process may not only exacerbate atherosclerosis, but also contribute to T cell-mediated inflammatory diseases in the hypercholesterolemia setting.

Adipose Tissue Macrophages in Rheumatoid Arthritis: Prevalence, Disease-Related Indicators, and Associations With Cardiometabolic Risk Factors.

OBJECTIVE: Adipose tissue macrophages (ATMs) are a potent source of inflammatory cytokines, with profound effects on adipose tissue function, yet their potential role in rheumatoid arthritis (RA) pathobiology is largely unstudied. METHODS: Periumbilical subcutaneous adipose tissue was obtained from 36 RA patients and 22 non-RA controls frequency matched on demographics and body mass index. Samples were stained for the macrophage marker CD68, and the average proportions of ATMs, crown-like structures (periadipocyte aggregates of 3 or more ATMs), and fibrosis were compared between groups. RESULTS: The adjusted proportion of ATMs among all nucleated cells was 76% higher in RA than in non-RA samples (37.7 versus 21.3%, respectively; P < 0.001), and the adjusted average number of crown-like structures was more than 1.5-fold higher in the RA group than in controls (0.58 versus 0.23 crown-like structure/high-power field, respectively; P = 0.001). ATMs were significantly more abundant in early RA and in those with anti-cyclic citrullinated peptide seropositivity. Users of methotrexate, leflunomide, and tumor necrosis factor inhibitors had a significantly lower proportion of ATMs compared with nonusers. Crown-like structures were significantly higher in patients with rheumatoid factor seropositivity and in those with C-reactive protein levels ≥10 mg/liter, and significantly lower among those treated with statins. Linear ATMs were significantly associated with whole-body insulin resistance, but not with serum lipids. CONCLUSIONS: ATMs and crown-like structures were more abundant in RA patients and were associated with systemic inflammation, autoimmunity, and whole-body insulin resistance, suggesting possible contributions to the RA disease process. Lower levels of ATMs and crown-like structures associated with specific RA treatments suggest that adipose tissue inflammation may be ameliorated by immunomodulation.

HSC extrinsic sex-related and intrinsic autoimmune disease-related human B-cell variation is recapitulated in humanized mice.

B cells play a major role in antigen presentation and antibody production in the development of autoimmune diseases, and some of these diseases disproportionally occur in females. Moreover, immune responses tend to be stronger in female vs male humans and mice. Because it is challenging to distinguish intrinsic from extrinsic influences on human immune responses, we used a personalized immune (PI) humanized mouse model, in which immune systems were generated de novo from adult human hematopoietic stem cells (HSCs) in immunodeficient mice. We assessed the effect of recipient sex and of donor autoimmune diseases (type 1 diabetes [T1D] and rheumatoid arthritis [RA]) on human B-cell development in PI mice. We observed that human B-cell levels were increased in female recipients regardless of the source of human HSCs or the strain of immunodeficient recipient mice. Moreover, mice injected with T1D- or RA-derived HSCs displayed B-cell abnormalities compared with healthy control HSC-derived mice, including altered B-cell levels, increased proportions of mature B cells and reduced CD19 expression. Our study revealed an HSC-extrinsic effect of recipient sex on human B-cell reconstitution. Moreover, the PI humanized mouse model revealed HSC-intrinsic defects in central B-cell tolerance that recapitulated those in patients with autoimmune diseases. These results demonstrate the utility of humanized mouse models as a tool to better understand human immune cell development and regulation.

Clinical and genetic associations of radiographic sacroiliitis and its different patterns in psoriatic arthritis.

OBJECTIVES: We aimed to 1) identify clinical and genetic associations of sacroiliitis (SI) in patients with psoriatic arthritis (PsA), and 2) describe the different radiographic patterns of SI in PsA and their clinical and genetic associations. METHODS: 283 PsA patients, fulfilling CASPAR criteria, underwent detailed skin and rheumatologic assessments. In addition, HLA-B*27 and B*080101 status was recorded, which have been shown as the key genetic markers of radiographic SI in PsA. Grade 2 Unilateral or bilateral radiographic changes of SI were required for inclusion and involvement was further defined as asymmetrical or symmetrical. RESULTS: 70 patients (25%) had radiographic SI; all either with a present or past history of backache. Regression analysis demonstrated a significant association of SI with peripheral joint erosions (p=0.043), PASI maximum (p=0.041), younger age of PsA onset (p=<0.001), presence of HLA-B*0801 (p=0.002) and only marginal significance with HLA-B*2705 (p=0.059). Asymmetrical SI was noted in 51 patients (73%). In striking contrast to those patients with symmetrical SI, patients with asymmetrical SI were more likely to be female (p=0.04), have a trend towards more severe nail disease (p=0.08) and peripheral joint erosions (p=0.08), more osteolysis (p=0.01), more HLA-B*0801 positivity (p=0.001) and much less HLA-B*270502 positivity (p=<0.001). CONCLUSIONS: PsA developing at a younger age, severe skin disease, peripheral joint erosions, and HLA-B*0801 are significantly associated with SI, and there was only a marginal trend towards significance for HLA-B*2705. HLA-B*27 positive Axial-PsA patients resemble AS, while HLA-B*0801 positive Axial-PsA patients have asymmetrical and/or unilateral SI, which are typical of PsA.

Axial Disease in Psoriatic Arthritis study: defining the clinical and radiographic phenotype of psoriatic spondyloarthritis.

OBJECTIVES: To compare the prevalence, clinical and radiographic characteristics of psoriatic spondyloarthritis (PsSpA) in psoriatic arthritis (PsA), with ankylosing spondylitis (AS). METHODS: A prospective single-centre cross-sectional observational study recruited consecutive PsA and AS cases. Participants completed outcome measures, and underwent clinical examination, axial radiographic scoring and HLA-sequencing. Multivariable analyses are presented. RESULTS: The 402 enrolled cases (201 PsA, 201 AS; fulfilling classification criteria for respective conditions) were reclassified based upon radiographic axial disease and psoriasis, as: 118 PsSpA, 127 peripheral-only PsA (pPsA), and 157 AS without psoriasis (AS) cases. A significant proportion of patients with radiographic axial disease had PsSpA (118/275; 42.91%), and often had symptomatically silent axial disease (30/118; 25.42%). Modified New York criteria for AS were fulfilled by 48/201 (23.88%) PsA cases, and Classification of Psoriatic Arthritis criteria by 49/201 (24.38%) AS cases. pPsA compared with PsSpA cases had a lower frequency of HLA-B*27 (OR 0.12; 95% CI 0.05 to 0.25). Disease activity, metrology and disability were comparable in PsSpA and AS. A significant proportion of PsSpA cases had spondylitis without sacroiliitis (39/118; 33.05%); they less frequently carried HLA-B*27 (OR 0.11; 95% CI 0.04 to 0.33). Sacroiliac joint complete ankylosis (adjusted OR, ORadj 2.96; 95% CI 1.42 to 6.15) and bridging syndesmophytes (ORadj 2.78; 95% CI 1.49 to 5.18) were more likely in AS than PsSpA. Radiographic axial disease was more severe in AS than PsSpA (Psoriatic Arthritis Spondylitis Radiology Index Score: adjusted incidence risk ratio 1.13; 95% CI 1.09 to 1.19). CONCLUSIONS: In a combined cohort of patients with either PsA or AS from a single centre, 24% fulfilled classification criteria for both conditions. The pattern of axial disease was influenced significantly by the presence of skin psoriasis and HLA-B*27.

Certain class I HLA alleles and haplotypes implicated in susceptibility play a role in determining specific features of the psoriatic arthritis phenotype.

OBJECTIVES: Psoriatic arthritis (PsA) susceptibility is associated with several different class I alleles, suggesting separate patterns of MHC effect. This exploratory study was based on the hypothesis that heterogeneity of the clinical phenotype of PsA might be explained by differing associations of clinical features with these susceptibility genes. METHODS: The clinical phenotype of 282 PsA patients in a cohort previously studied for associations with human leukocyte antigen (HLA)-B and HLA-C genotypes was first preliminarily assessed by univariate associations of susceptibility genes with specific clinical characteristics. To explore the potential genotypic effects of pairwise combinations of different HLA-B and C alleles/haplotypes, we created a series of allele/haplotype risk scores combining single alleles/haplotypes separately associated with being in the highest PsA severity propensity tertile based on the features studied by univariate analysis. RESULTS: In exploratory univariate analyses, B*27:05:02 was positively associated with enthesitis, dactylitis and symmetric sacroiliitis, whereas B*08:01:01-C*07:01:01and its component alleles were positively associated with joint fusion and deformities, asymmetrical sacroiliitis, and dactylitis. HLA-C*06:02:01 was negatively associated with asymmetrical sacroiliitis. The highest propensity score for severe PsA was with B*27:05:02-C*02:02:02, B*08:01:01-C*07:01:01 and B*37:01:01-C*06:02:01, but not the B*27:05:02-C*01:01:01 or B*57:01:01-C*06:02:01 haplotypes. In contrast, B*44 haplotypes were associated with presence of milder disease, and in univariate analysis with a decreased frequency of enthesitis, joint fusion, deformities and dactylitis. CONCLUSIONS: Different HLA susceptibility genes were associated with particular features that defined the PsA phenotype of a given patient. Additive interactions between different susceptibility HLA alleles defined the propensity for a more severe or milder musculoskeletal phenotype.

Concepts of pathogenesis in psoriatic arthritis: genotype determines clinical phenotype.

This review focuses on the genetic features of psoriatic arthritis (PsA) and their relationship to phenotypic heterogeneity in the disease, and addresses three questions: what do the recent studies on human leukocyte antigen (HLA) tell us about the genetic relationship between cutaneous psoriasis (PsO) and PsA - that is, is PsO a unitary phenotype; is PsA a genetically heterogeneous or homogeneous entity; and do the genetic factors implicated in determining susceptibility to PsA predict clinical phenotype? We first discuss the results from comparing the HLA typing of two PsO cohorts: one cohort providing the dermatologic perspective, consisting of patients with PsO without evidence of arthritic disease; and the second cohort providing the rheumatologic perspective, consisting of patients with PsA. We show that these two cohorts differ considerably in their predominant HLA alleles, indicating the heterogeneity of the overall PsO phenotype. Moreover, the genotype of patients in the PsA cohort was shown to be heterogeneous with significant elevations in the frequency of haplotypes containing HLA-B*08, HLA-C*06:02, HLA-B*27, HLA-B*38 and HLA-B*39. Because different genetic susceptibility genes imply different disease mechanisms, and possibly different clinical courses and therapeutic responses, we then review the evidence for a phenotypic difference among patients with PsA who have inherited different HLA alleles. We provide evidence that different alleles and, more importantly, different haplotypes implicated in determining PsA susceptibility are associated with different phenotypic characteristics that appear to be subphenotypes. The implication of these findings for the overall pathophysiologic mechanisms involved in PsA is discussed with specific reference to their bearing on the discussion of whether PsA is conceptualised as an autoimmune process or one that is based on entheseal responses.

Association of fine specificity and repertoire expansion of anticitrullinated peptide antibodies with rheumatoid arthritis associated interstitial lung disease.

BACKGROUND: Interstitial lung disease (ILD) is associated with high morbidity and mortality in rheumatoid arthritis (RA). Citrullinated proteins are observed in RA lung tissues; however, the association of specific anticitrullinated peptide antibodies (ACPA) with ILD in RA is unknown. METHODS: RA patients underwent multidetector CT (MDCT) of the chest, from which ILD features and a semiquantitative ILD Score (ILDS; range 0-32) were assessed. Anti-CCP (CCP2) and levels of a panel of antibodies against 17 citrullinated and four non-citrullinated peptides were assessed from concurrent serum samples using a custom Bio-Plex bead array. High level ACPA was defined as ≥the group 75th percentile. RESULTS: Among the 177 RA patients studied, median levels of CCP2 and all specific ACPAs were 46-273% higher among RA patients with versus those without ILD (all p values <0.05), and higher levels correlated with higher ILDS. In contrast, levels of non-citrullinated protein antibodies were not higher in those with ILD. RA patients had a median of 2 high level ACPA reactivities (range 0-16), with each high level ACPA associated, on average, with a 0.10 unit higher ILDS (p=0.001). This association remained significant after adjusting for characteristics associated with ILD (age, gender, current and former smoking, Disease Activity Score for 28 joints, current prednisone and leflunomide use). More high level ACPA were observed in those with versus without pulmonary function restriction or impaired diffusion. CONCLUSIONS: Our findings of a broader ACPA repertoire in RA ILD suggest a possible role for ACPA in the pathogenesis of ILD.