Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis and Goodpasture’s disease, is associated with particular Human Leukocyte Antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigated the molecular mechanism of Goodpasture’s disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4+ T cell self-epitope derived from the α3 chain of Type IV collagen (α3135-145)1–4. While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective in trans with HLA-DR152. We show that autoreactive α3135-145-specific T cells expand in patients with Goodpasture’s disease and, in α3135-145-immunized HLA-DR15 transgenic mice, α3135-145-specific T cells infiltrate the kidney and mice develop Goodpasture’s disease. HLA-DR15 and HLA-DR1 exhibited distinct peptide repertoires and binding preferences and presented the α3135-145 epitope in different binding registers. HLA-DR15-α3135-145 tetramer+ T cells in HLA-DR15 transgenic mice exhibit a conventional T cell phenotype (Tconv) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-α3135-145 tetramer+ T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4+Foxp3+ regulatory T cells (Tregs) expressing tolerogenic cytokines. HLA-DR1-induced Tregs confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15+ and HLA-DR1+ healthy human donors displayed altered α3135-145-specific TCR usage, HLA-DR15-α3135-145 tetramer+ Foxp3− Tconv and HLA-DR1-α3135-145 tetramer+ Foxp3+CD25hiCD127lo Treg dominant phenotypes, and patients with Goodpasture’s disease display a clonally expanded α3135-145-specific CD4+ T cell repertoire. Accordingly, we provide a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease, whereby HLA polymorphism shapes the relative abundance of self-epitope specific Tregs that leads to protection or causation of autoimmunity.

Genes in the major histocompatibility complex (MHC) encode proteins important in activating antigen-specific immune responses. Alleles at adjacent MHC loci are often in strong linkage disequilibrium; however, little is known about the mechanisms responsible for this linkage disequilibrium. Here we report that the human MHC HLA-DR2 haplotype, which predisposes to multiple sclerosis, shows more extensive linkage disequilibrium than other common caucasian HLA haplotypes in the DR region and thus seems likely to have been maintained through positive selection. Characterization of two multiple-sclerosis-associated HLA-DR alleles at separate loci by a functional assay in humanized mice indicates that the linkage disequilibrium between the two alleles may be due to a functional epistatic interaction, whereby one allele modifies the T-cell response activated by the second allele through activation-induced cell death. This functional epistasis is associated with a milder form of multiple-sclerosis-like disease. Such epistatic interaction might prove to be an important general mechanism for modifying exuberant immune responses that are deleterious to the host and could also help to explain the strong linkage disequilibrium in this and perhaps other HLA haplotypes.

Environmental factors account for 75% of the risk of developing multiple sclerosis (MS). Numerous infections have been suspected as environmental disease triggers, but none of them has consistently been incriminated, and it is unclear how so many different infections may play a role. We show that a microbial peptide, common to several major classes of bacteria, can induce MS-like disease in humanized mice by crossreacting with a T cell receptor (TCR) that also recognizes a peptide from myelin basic protein, a candidate MS autoantigen. Structural analysis demonstrates this crossreactivity is due to structural mimicry of a binding hotspot shared by self and microbial antigens, rather than to degenerate TCR recognition. Biophysical studies reveal that the autoreactive TCR binding affinity is markedly lower for the microbial (mimicry) peptide than for the autoantigenic peptide. Thus, these data suggest a possible explanation for the difficulty in incriminating individual infections in the development of MS.

Background An increased incidence of thromboembolic events (TE) are reported in nephrotic syndrome (NS) leading to recommendations for prophylactic anticoagulation (PAC). However, as no randomized clinical trial has established the efficacy or risks associated with PAC, guidelines are empiric or substantiated only by estimates of risks and benefits. This study evaluates the risk of TE and hemorrhagic complications in patients with NS treated with PAC and compares to patients not receiving PAC. Methods We included patients diagnosed with NS from two Danish nephrology departments with different practices for the use of PAC. Patients were included if presenting with NS from September 2006 to January 2012, a P-albumin < 30 g/L, and renal biopsy confirming non-diabetic, glomerular disease. Patients aged < 16 years, on renal replacement therapy, or administered anticoagulants at the onset of NS were excluded. Bleeding episodes and/or TE were identified from patient records. Bleeding episodes were divided into minor and major bleeding. Results Of the 79 patients included, 44 patients received PAC either as low or high dose low-molecular-weight heparin (LMWH) or as warfarin with or without LMWH as bridging, while 35 did not receive PAC. P-albumin was significant lower in the PAC group compared to those not receiving PAC. Significantly more TEs was observed in the non-PAC group compared to the PAC group (4 versus 0 episodes, P = 0.035). The TEs observed included one patient with pulmonary embolism (PE), one with PE and deep vein thrombosis, one with PE and renal vein thrombosis, and one with a stroke. Five patients with bleeding episodes were identified among those receiving PAC, of which two were major and three were minor, while two patients in the non-PAC group experienced a minor bleeding episode ( P = 0.45 between groups). The major bleeding episodes only occurred in patients receiving PAC in combination with low dose aspirin. Conclusions In patients with NS the use of PAC was associated with a decreased risk of clinically significant TE, but may also be associated with more bleeding episodes although not statistically significant. Only patients treated with PAC in combination with anti-platelet therapy had major bleeding episodes.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is clinically heterogeneous and affects multiple organs. Lupus nephritis is the most frequent severe manifestation of SLE. Conventional immunosuppressive therapy has increased the life expectancy of patients diagnosed with lupus nephritis, but only 70-80% of patients respond to this treatment and its adverse effects are considerable. B cells are central to the pathogenesis of SLE and are, therefore, an attractive therapeutic target. B-cell depletion has been used successfully to treat other autoimmune diseases, such as rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis, and many case reports and small nonrandomized trials of B-cell-depleting agents in patients with lupus nephritis have reported positive results. By contrast, two large placebo-controlled trials designed to investigate the efficacy of the B-cell-depleting agents rituximab and ocrelizumab as a treatment for lupus nephritis, failed to meet their primary efficacy end points (LUNAR and BELONG, respectively). This Review discusses the current evidence on the use of B-cell depletion in the treatment of lupus nephritis, which is derived from case studies and clinical trials including a total of over 800 patients.