Attenuated immune control of Epstein-Barr virus in humanized mice is associated with the multiple sclerosis risk factor HLA-DR15.

Immune responses to Epstein-Barr virus (EBV) infection synergize with the main genetic risk factor HLA-DRB1*15:01 (HLA-DR15) to increase the likelihood to develop the autoimmune disease multiple sclerosis (MS) at least sevenfold. In order to gain insights into this synergy, we investigated HLA-DR15 positive human immune compartments after reconstitution in immune-compromised mice (humanized mice) with and without EBV infection. We detected elevated activation of both CD4+ and CD8+ T cells in HLA-DR15 donor-reconstituted humanized mice at steady state, even when compared to immune compartments carrying HLA-DRB1*04:01 (HLA-DR4), which is associated with other autoimmune diseases. Increased CD8+ T cell expansion and activation was also observed in HLA-DR15 donor-reconstituted humanized mice after EBV infection. Despite this higher immune activation, EBV viral loads were less well controlled in the context of HLA-DR15. Indeed, HLA-DR15-restricted CD4+ T cell clones recognized EBV-transformed B cell lines less efficiently and demonstrated cross-reactivity toward allogeneic target cells and one MS autoantigen. These findings suggest that EBV as one of the main environmental risk factors and HLA-DR15 as the main genetic risk factor for MS synergize by priming hyperreactive T-cell compartments, which then control the viral infection less efficiently and contain cross-reactive CD4+ T cell clones.

Muscle-Specific Kinase Myasthenia Gravis.

Thirty to fifty percent of patients with acetylcholine receptor (AChR) antibody (Ab)-negative myasthenia gravis (MG) have Abs to muscle specific kinase (MuSK) and are referred to as having MuSK-MG. MuSK is a 100 kD single-pass post-synaptic transmembrane receptor tyrosine kinase crucial to the development and maintenance of the neuromuscular junction. The Abs in MuSK-MG are predominantly of the IgG4 immunoglobulin subclass. MuSK-MG differs from AChR-MG, in exhibiting more focal muscle involvement, including neck, shoulder, facial and bulbar-innervated muscles, as well as wasting of the involved muscles. MuSK-MG is highly associated with the HLA DR14-DQ5 haplotype and occurs predominantly in females with onset in the fourth decade of life. Some of the standard treatments of AChR-MG have been found to have limited effectiveness in MuSK-MG, including thymectomy and cholinesterase inhibitors. Therefore, current treatment involves immunosuppression, primarily by corticosteroids. In addition, patients respond especially well to B cell depletion agents, e.g., rituximab, with long-term remissions. Future treatments will likely derive from the ongoing analysis of the pathogenic mechanisms underlying this disease, including histologic and physiologic studies of the neuromuscular junction in patients as well as information derived from the development and study of animal models of the disease.

Human leucocyte antigen DR15, a possible predictive marker for immune checkpoint inhibitor-induced secondary adrenal insufficiency.

BACKGROUND: Immune checkpoint inhibitors (ICPis) induce various immune-related adverse events (irAEs), despite their beneficial effects in treating various advanced cancers. ICPi-induced secondary adrenal insufficiency is described as a prevalent and serious 'pituitary irAE.' However, its precise mechanism remains unclear, and no definitive predictive markers have been reported. PATIENTS AND METHODS: We enrolled and studied 11 patients with advanced cancer (aged 39-70 years; 6 male patients) receiving nivolumab, pembrolizumab or ipilimumab who developed pituitary irAEs. Their clinical data, including endocrine functions, were retrospectively assessed and human leucocyte antigen (HLA) genotypes were determined to compare the HLA allele frequencies in these patients and healthy controls. RESULTS: Among 11 patients, 7, 3 and 1 patients exhibited malignant melanoma, non-small-cell lung cancer and gastric cancer, respectively. HLA type screening results revealed that HLA-DR15, B52 and Cw12 were observed in 9, 7, and 7 patients with pituitary irAE, respectively. DR15, B52 and Cw12 were significantly more prevalent in our group than in the healthy control group from the Japanese HLA-haplotype database (this study vs healthy control group); DR15: 81.8% vs 33.5% (n = 11, P = 0.0014), B52: 63.6% vs 21.0% (n = 11, P = 0.0026) and Cw12: 70% vs 21.3% (n = 10, P = 0.0013). CONCLUSIONS: HLA-DR15, B52 and Cw12 are possible predisposing factors for pituitary irAEs. HLA-DR15 is reportedly associated with autoimmune disease via interleukin-17 regulation, suggesting its involvement in pituitary irAE development. Using HLA haplotypes as pituitary irAE predictive markers, we could provide safe ICPi treatment and understand irAE pathogenesis.

SF3B1 Mutations Negatively Predict for Response to Immunosuppressive Therapy in Myelodysplastic Syndromes.

BACKGROUND: Immunosuppressive therapy (IST) yields durable hematologic improvement (HI) in a subset of patients with lower-risk myelodysplastic syndrome (MDS). Age, human leukocyte antigen (HLA)-DR15 positivity, and duration of transfusion dependence are putative clinical variables predictive for response. We investigated the effect of somatic gene mutations on response to IST in lower-risk MDS. PATIENTS AND METHODS: Forty of 66 patients who received antithymocyte globulin with or without cyclosporine A identified at the Moffitt Cancer Center were molecularly profiled using a 49-gene myeloid panel. All patients profiled received antithymocyte globulin, and cyclosporine A was provided to 60% of patients. RESULTS: The overall frequency of HI was 42%. Presence of a large granular lymphocytic clone, hypocellular bone marrow, HLA-DR15 positivity, trisomy 8, and age had no influence on response to IST. Among 40 patients evaluated by next-generation sequencing, the presence of an SF3B1 mutation (MT) was significantly associated with IST nonresponse (1 of 9 SF3B1 MT, 11% vs. 21 of 31 wild type, 68%; P = .002). All patients with SF3B1 MT had ring sideroblasts > 15% (RS) by morphology; the corresponding HI rate was 20% among patients with RS versus 50% for those without RS (P = .09). CONCLUSION: These findings support the clinical implementation of genomics in MDS. The presence of an SF3B1 mutation adversely influences response to IST and should be incorporated into treatment decisions upon validation of these findings.

HLA-DR15-specific inhibition attenuates autoreactivity to the Goodpasture antigen.

Goodpasture's disease manifests as rapidly progressive glomerulonephritis. Current immunosuppressive treatments do not specifically target the pathological immune response and have significant side effects. Like most autoimmune diseases, the strongest genetic association is with the HLA alleles. Inheritance of HLA-DR15 confers susceptibility, and structure-function studies have shown that HLA-DR15 plays a causative role in activating autoreactive pro-inflammatory T cells. Thus, specific inhibition of HLA-DR15 would provide a targeted therapeutic approach. We hypothesised that PV-267, an HLA-DR15-specific inhibitor, would effectively block HLA-DR15 presentation of the dominant epitope, attenuate the activation of autoreactive T cells, and limit disease. Using humanised HLA-DR15 transgenic mice, α3135-145-specific, pro-inflammatory T cell recall responses were measured using IFN-γ and IL-17A ELISPOTs and by proliferation assay. To determine if PV-267 could limit disease, experimental autoimmune anti-GBM glomerulonephritis was induced in HLA-DR15 transgenic mice (on an Fcgr2b-/- background), and functional and histological disease endpoints were measured. PV-267 effectively inhibited α3135-145-specific immune responses and disease development. Mice treated prior to immunization with α3135-145 had reduced α3135-145-specific recall responses, and limited disease by albuminuria, histological glomerular injury, IgG deposition, and inflammatory cell infiltrates. PV-267 treatment commencing after the onset of active anti-α3(IV)NC1 autoimmunity attenuated functional and histological renal injury. When treatment was administered after disease was established, PV-267 limited the severity of histological injury. In conclusion, HLA-DR15 inhibition attenuates α3(IV)NC1-specific pro-inflammatory responses and could be used as an adjunct therapy for anti-GBM disease.

The Presence of HLA-B75, DR13 Homozygosity, or DR14 Additionally Increases the Risk of Allopurinol-Induced Severe Cutaneous Adverse Reactions in HLA-B*58:01 Carriers.

BACKGROUND: Although HLA-B*58:01 is a well-known risk factor for the development of allopurinol-induced severe cutaneous adverse reactions (SCARs), most of the HLA-B*58:01 carriers do not suffer from SCARs despite a long-term use of allopurinol. This suggests that there are other risk factors that determine the fate of HLA-B*58:01 carriers. OBJECTIVE: The aim of this study was to investigate the additional genetic factors that increase the risk of allopurinol-induced SCARs in HLA-B*58:01 carriers. METHODS: The incidence of allopurinol-induced SCARs was investigated according to coexisting HLA alleles in all subjects with HLA-B*58:01 who took allopurinol between 2003 and 2017. The allopurinol tolerant group was defined as a group who took allopurinol for more than 60 days without developing hypersensitivity and was compared with the allopurinol-induced SCAR group. RESULTS: Among the retrospective cohort consisting of 367 HLA-B*58:01 carriers treated with allopurinol, 11 (3.0%) were diagnosed with allopurinol-induced SCARs. When HLA-B75, DR13 homozygosity, or DR14 was present, the incidence of SCARs increased up to 22.2% (odds ratio [OR], 19.568; P = .015), 20.0% (OR, 38.458; P = .001), and 10.7% (OR, 19.355; P = .004), respectively. Among the 153 HLA-B*58:01 carriers with chronic renal insufficiency (CRI), the incidence of SCARs doubled to 6.5% and further increased to 40%, 30%, and 37.5% in the presence of HLA-B75, DR13 homozygosity, or DR14, respectively. CONCLUSIONS: Secondary screening with HLA-B75, DR13 homozygosity, and DR14 in addition to primary screening with HLA-B*58:01 would enable a more accurate prediction of SCAR occurrence, especially in patients with CRI.

Engineered MBP-specific human Tregs ameliorate MOG-induced EAE through IL-2-triggered inhibition of effector T cells.

Expanded polyclonal T regulatory cells (Tregs) offer great promise for the treatment of immune-mediated diseases. Inhibition by Tregs is under the control of the T-cell receptor (TCR). Therefore, we created Tregs with defined antigen specificity, using a recombinant T-cell receptor isolated from a myelin-basic protein specific T-cell clone of a multiple sclerosis (MS) patient (Ob2F3). We expressed this TCR using a retroviral expression vector in human Tregs from peripheral blood. We observed that transduced Tregs were activated in vitro in response to myelin basic protein (MBP) peptide on DR15 antigen-presenting cells (APC) and upregulated Treg markers, Foxp3, LAP and Helios. These engineered MBP-specific Tregs could suppress MBP-specific T effector cells, and were also able to suppress T cells with other specificities after Tregs had been activated through the TCR. Importantly, we showed that these engineered Tregs were able to function effectively in the presence of strong TLR-induced inflammatory signals, and that MBP-specific Tregs ameliorated EAE in myelin oligodendrocyte glycoprotein (MOG)-immunized DR15 transgenic mice. We further demonstrated in vitro that IL-2 produced by neighboring effector T cells activated MBP-specific Tregs, initiating contact-independent suppression to T effectors in local milieu. Mechanistic studies demonstrated that bystander suppression in vivo may involve transfer of soluble mediators, enhanced by cell contact between Tregs and effectors. Taken together, we show that engineered clonal MBP-specific Tregs are able to suppress autoimmune pathology in EAE. This approach may serve as a cellular therapy for MS patients with the common DR15 haplotype that is associated with disease susceptibility.

TCR Vß Usage of Peripheral Blood and Liver Infiltrating Lymphocytes in Patients with Chronic Hepatitis B.

INTRODUCTION: Chronic hepatitis B (CHB) is still a public health problem and its mechanism remains unclear. In this study, we detect the skewness of T cell receptor beta chain variable gene (TCR Vß) in peripheral blood lymphocytes (PBL) and the liver infiltrating lymphocytes (LIL) of patients with CHB; and hope to provide information for further research on the pathogenic mechanism of CHB. MATERIAL AND METHODS: Fifteen patients with CHB, ten healthy volunteers and three patients with liver cysts were recruited as the subjects. The usage of TCR Vß of PBL and LIL were measured and compared; the associations of the TCR Vß usage of PBL with some hematological indices, including human leukocyte antigen (HLA) alleles, percents of CD4+ and CD8+ T cells, sera levels of HBV-DNA and IFN-γ, were analyzed. RESULTS: In PBL, Vß12 and Vß13.1 were the highest predominant usage genes which usage frequencies were all 46.7%; Vß23 was the key limited usage gene (40.0%). In LIL, the mainly predominant and limited usage gene was Vß13.1 (73.3%) and Vß23 (46.7%), respectively. About half of the patients with CHB with HLA-DR9 or HLA-DR12 showed the predominant usage of Vß5.2 or Vß13.2. In patients with CHB, the percentage of CD4+ T cells was 33.41 ± 5.39 %, that of CD8+ T cells was 28.67 ± 6.77 %; the concentration of IFN-γ was 182.52 ± 44.16 pg/mL. Compared to the healthy controls, there were significant differences for these data (P < 0.05). Neither ALT nor HBV-DNA was relative to the usage of TCR Vß. CONCLUSIONS: PBL and LIL share the common sknewness of TCR Vß genes, which probably relates to some hematological indices. However, the roles of such similarities and associations in the development of CHB need further study.

Population attributable fractions and joint effects of key risk factors for multiple sclerosis.

AIM: We examined the combined effect of having multiple key risk factors and the interactions between the key risk factors of multiple sclerosis (MS). METHODS: We performed an incident case-control study including cases with a first clinical diagnosis of central nervous system demyelination (FCD) and population-based controls. RESULTS: Compared to those without any risk factors, those with one, two, three, and four or five risk factors had increased odds of being an FCD case of 2.12 (95% confidence interval (CI), 1.11-4.03), 4.31 (95% CI, 2.24-8.31), 7.96 (95% CI, 3.84-16.49), and 21.24 (95% CI, 5.48-82.40), respectively. Only HLA-DR15 and history of infectious mononucleosis interacted significantly on the additive scale (Synergy index, 3.78; p = 0.03). The five key risk factors jointly accounted for 63.8% (95% CI, 43.9-91.4) of FCD onset. High anti-EBNA IgG was another important contributor. CONCLUSIONS: A high proportion of FCD onset can be explained by the currently known risk factors, with HLA-DR15, ever smoking and low cumulative sun exposure explaining most. We identified a significant interaction between HLA-DR15 and history of IM in predicting an FCD of CNS demyelination, which together with previous observations suggests that this is a true interaction.

Phosphorylated alpha-enolase induces autoantibodies in HLA-DR8 pancreatic cancer patients and triggers HLA-DR8 restricted T-cell activation.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer-induced death in the Western World. In PDAC patients, alpha-enolase (ENOA), a glycolytic enzyme that also acts as plasminogen receptor, is up-regulated and elicits the production of autoantibodies. Our previous studies revealed that most PDAC patients specifically produce antibodies to Serine(419)phosphorylated ENOA (Ser(419)P-ENOA) isoforms (ENOA1,2), and that this humoral response correlates with a better clinical outcome. Since autoantibody production can be influenced by HLA polymorphisms, and the ENOA sequence presents multiple peptides predicted to preferentially bind HLA-DR molecules, including the peptide containing Ser(419), we hypothesized that the presence of autoantibodies against ENOA1,2 is associated with specific HLA-DRB1 alleles. Here, we demonstrate that the HLA-DRB1*08 allele is significantly more frequent in PDAC patients with autoantibodies to ENOA1,2 (ENOA1,2(+), 8%) compared to healthy controls (3%, p=0.0112). We observed that a Ser(419)P-ENOA peptide, bioinformatically predicted to bind with high affinity to the HLA-DR8 allele coded by HLA-DRB1*08:01 or *08:04 alleles, was able to activate specific CD4(+) T cell clones derived from a HLA-DRB1*08:01. Thus complexes of the Ser(419)P-ENOA peptide with the HLA that trigger T-cell signaling might be relevant for induction of anti-tumor immune response.

Risk factors for multiple sclerosis, neuromyelitis optica and transverse myelitis.

BACKGROUND: Little is known about risk factors for neuromyelitis optica (NMO) or transverse myelitis (TM). OBJECTIVE: The objective of this paper is to evaluate whether established multiple sclerosis (MS) risk factors, including smoking history, a history of infectious mononucleosis (IM), anti-EBNA1 Ab titers and HLA-DR15 are associated with NMO or TM. METHODS: We conducted a case-control study among participants in the Accelerated Cure Project for Multiple Sclerosis (ACP) Repository, which includes patients with MS, NMO and TM. Controls include related and unrelated individuals without evidence of demyelinating disease. Analyses included 1237 cases of MS, 98 cases of NMO, 133 cases of TM and 488 healthy controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to assess the association between smoking, HLA-DR15, anti-EBNA1 Ab titers and a history of IM adjusting for gender, study site and ethnicity. RESULTS: Overall, the association between smoking, IM, HLA-DR15 and anti-EBNA1 Ab titers and odds of MS were as expected and no significant interactions were observed. However, there was little evidence of association between these MS risk factors and odds of NMO or TM. CONCLUSIONS: Established MS risk factors do not appear to be associated with susceptibility to TM or NMO and, among MS patients, these risk factors appear to act independently.

A Japanese patient with Löfgren's syndrome with an HLA-DR12 allele and review of literature on Japanese patients.

Sarcoidosis is a granulomatous disorder of unknown etiology, with several clinical manifestations. Löfgren's syndrome is an acute type of sarcoidosis, characterized by the triad of arthritis, erythema nodosum, and bilateral hilar lymphadenopathy (BHL), which spontaneously resolve within about 2 years. Löfgren's syndrome is common among young white women from Nordic countries and Ireland, but it is very rare in Japan. Because the incidence of Löfgren's syndrome varies according to race, most studies on Löfgren's syndrome, including HLA typing, have been reported in Western countries. Indeed, HLA-DR3 has been reported to be associated with Löfgren's syndrome in Western countries, although the association between HLA typing and Japanese Löfgren's syndrome remains unclear. Here we present a Japanese patient with Löfgren's syndrome. A 34-year-old female patient was hospitalized with arthritis and erythema nodosum. Chest computed tomography revealed mediastinal and BHL. Endobronchial ultrasound-guided transbronchial needle aspiration showed non-caseating epithelioid cell granulomas. Löfgren's syndrome was thus diagnosed. Her ankle arthralgia and bilateral ankle swelling recovered without steroid treatment within two months, and the BHL almost completely diminished one year after admission. Her HLA genotype contains DR12. We also reviewed the literature on 11 Japanese patients with Löfgren's syndrome, showing that HLA-DR12 is present in five out of nine patients (55.6%). The relevant data were unavailable in the remaining three patients. Importantly, only 5.4% of registered donors in the Japan Marrow Donor Program are positive for this allele. We suggest the potential link between HLA-DR12 and the pathogenesis of Löfgren's syndrome in Japanese patients.

HLA-DR9 and DR14 are associated with the allopurinol-induced hypersensitivity in hematologic malignancy.

Allopurinol, a widely used urate-lowering agent, is a leading cause of severe cutaneous adverse reactions (SCARs), especially in patients with HLA-B*58:01. Despite its routine use for the prevention of tumor lysis-related hyperuricemia prior to chemotherapy, the risk of allopurinol-induced hypersensitivity has not been investigated in patients with hematologic malignancies. This retrospective cohort study was conducted to investigate the incidence and risk factors of allopurinol-induced hypersensitivity in patients at least 18 years of age with hematologic malignancies. We reviewed 463 patients who had ever taken allopurinol for the prevention of hyperuricemia prior to chemotherapy and had undergone serologic HLA typing as a pre-transplant evaluation from January 2000 to May 2010. Thirteen (2.8%) patients experienced maculopapular eruptions (MPE) and none experienced SCARs. Among subtypes of underlying hematologic malignancies, percentage of chronic myeloid leukemia was significantly higher in the allopurinol hypersensitivity group compared with the tolerant group (23.1% (3/13) vs. 5.9% (26/440), P = 0.044). According to HLA subtypes, the incidence of allopurinol-induced MPE was 4.0% in HLA-B58 (+) patients (2/50) and 2.7% in HLA-B58 (-) patients (11/403) but this difference was statistically insignificant. In contrast to HLA-B58, the frequencies of DR9 and DR14 were significantly higher in the allopurinol-induced MPE group compared with the allopurinol tolerant group (38.5% (5/13) vs. 13.6% (53/443), P = 0.019, and 38.5% (5/13) vs. 15.6% (41/440), P = 0.038, respectively). In conclusion, HLA-DR9 and DR14, but not HLA-B58, are associated with hypersensitivity reaction by allopurinol when administered in patients with hematologic malignancy prior to chemotherapy.

Interleukin-17 enhances the production of interferon-γ and tumour necrosis factor-α by bone marrow T lymphocytes from patients with lower risk myelodysplastic syndromes.

INTRODUCTION: Lower risk myelodysplastic syndromes (MDSs) are characterised by increased apoptosis of haematopoietic cells in the bone marrow (BM). The mechanism driving this excessive apoptosis involves multiple immune molecules, including inflammatory cytokines such as interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α) and interleukins (ILs). Interleukin-17 (IL-17) is the hallmark cytokine produced by CD4(+) Th17 cells, and IL-17 mediates activation of the adaptive T-cell response inducing an inflammatory cytokine environment. However, little is known about the role of IL-17 in MDS-associated immune dysfunction. METHODS: A total of 47 patients with myelodysplastic syndromes were enrolled in this study, and the levels of IL-17 and IL-17 receptor (IL-17R) in BM mononuclear cells (BMNCs) were detected by real-time polymerase chain reaction (RQ-PCR) and enzyme-linked immunosorbent assay (ELISA). Then, BMNCs were stimulated with recombinant human IL-17 (rhIL-17), and flow cytometry was used to analyse the production of IFN-γ and TNF-α by CD4(+) and CD(+) T lymphocytes from patients with lower-risk MDS. Characterisation of IL-17 expression in patients with the HLA-DR15 allele or hypocellularity was also performed. RESULTS: mRNA levels for both IL-17 and the IL-17R subunits in BMNCs and for IL-17 in the BM and plasma were higher in patients with lower-risk MDS as compared to patients with higher-risk MDS and normal controls. The production of IFN-γ and TNF-α by CD4(+) and CD8(+) T lymphocytes from patients with lower-risk MDS could be enhanced by recombinant human IL-17 (rhIL-17) treatment. Furthermore, increased IL-17 expression was associated with more severe anaemia in with patients with MDS. CONCLUSION: Elevated IL-17 levels and IL-17-induced IFN-γ and TNF-α overproduction may be involved in the pathogenesis of lower risk MDS.

Tumor rejection effects of allorestricted tumor peptide-specific CD4(+) T cells on human cervical cancer cell xenograft in nude mice.

Generation of tumor specific alloreactive CD4(+) T cells is important to circumvent tumor tolerance. Here, we generate allorestricted peptide-specific CD4(+) T cells by coculture of lymphocytes and autologous monocytes bearing allogeneic HLA-DR15 molecule associated with its restricted peptide. Binding of a dimeric HLA-DR15/IgG1-Fc fusion protein (the dimer) to HLA-DR15 negative (HLA-DR15-ve) monocytes made the monocytes coated with the allogeneic epitope. An increased proliferation of CD4(+) T cells and induction of Th1 cells appeared after coculturing of HLA-DR15-ve lymphocytes and the autologous monocytes loaded with the dimer. The cocultural bulks showed an increased frequency of the specific dimer-stained CD4(+) T cells and the expanded CD4(+) T cells exhibited an elevated IFN-γ production in response to specific TCR ligand. Tumor rejection effects of the allorestricted E7-specific CD4(+) T cells raised by the coculture were observed in nude mice challenged with human cervical cancer cell SiHa expressing both HLA-DR15 and E7 antigens, as the tumor avoidance and life span of the mice were improved after adoptive transfer of the CD4(+) T cells. This study may help to develop strategies to separate graft-versus-leukemia or graft-versus-tumor reaction from graft-versus-host disease, and add to the pool of human high-avidity TCRs specific for tumor or virus antigens.

Weak or absent evidence for the association of HLA-DR antigens with risk of thyroid carcinoma: a meta-analysis of observational studies.

Inconsistent reports of associations between human leukocyte antigen (HLA)-DR and thyroid cancers exist. We conducted a comprehensive search of the PubMed, Scopus and Web of Science databases. Using random-effects modeling, subgroup analyses, meta-regression and prediction interval (PI) estimation, we combined the existing evidence from 13 studies (977 cases of thyroid cancer and 3735 controls). Only HLA-DR1 and HLA-DR11 were significantly associated; however, the evidence for HLA-DR11 came from only three studies while that for HLA-DR1 had large between-study heterogeneity. All the PIs estimated in the study straddled unity. Therefore, current evidence for the studied association is incomplete as well as uncertain. Attempts to include HLA-DR typing as a prognostic or therapeutic marker may be premature at this time.