New auto[cross-reactive]-antigen, GDP-l-fucose synthase, identified in MS patients

Multiple sclerosis (MS) is a debilitating autoimmune disease affecting nervous system. Several auto-antigens have been traditionally suspected for MS pathology, mostly derived from neural tissues such myelin. However, more recently the list of relevant auto-antigens expanded to include such member as RAS guanyl releasing protein (RASGRP1–4) family. Similarly, a new paper in Science Translational Medicine presented evidence that yet another auto-antigen, GDP-l-fucose synthase, is a target antigen in a subset of MS patients.

The authors has used modified version of positional scanning epitope library to identify epitope derived from auto-antigen, GDP-L-fucose synthase, as a target epitope for CD4+ T cell clone, TCC21.1, derived from MS patients with DR15 haplotype. Peptides sequences matching GDP-l-fucose synthase was detected in brain tissue.

MS patients whose T cells displayed high response to peptides from GDP-L-fucose synthase in stimulation assay showed high responses to myelin proteins as well.

Curiously, almost all high responders carried DRB3*02:02 allele. 

Finally, the authors speculated that sequence similarity between human and microbiota-derived evolutionary conserved GDP-L-fucose synthase could be a factor that initiates MS pathology in these patients.

In summary, this study has a lot of nice data that support idea that GDP-L-fucose synthase is a  new auto-antigen that could be relevant in molecular diagnosis of MS pathology.

There are several questions about this study. GDP-L-fucose synthase expression is not restricted to brain tissue. So, it should be relevant to understand if other tissues were affected in those MS patients. Second, cross-reactivity per se is not sufficient to explain how and why autoimmune responses are being initiated. Microbiota expressing GDP-L-fucose synthase most likely reside in patients long before MS, maybe even since birth, and T cells are tolerant to them. So, what has to be changed, in a antigen-specific manner, to make T cells less tolerant to initiate specific autoimmune attack on nervous system and not a total autoimmunity targeting all available auto-antigens? 

posted by David Usharauli

ADAMTS-like protein 5 (ADAMTSL5) is a melanocyte-derived auto-antigen in psoriasis

Psoriasis is a chronic skin inflammatory disorder characterized by thickening of skin epidermal layer. Psoriasis is considered autoimmune diseases due to presence of activated T cells within epidermal layer in affected skin and clinical benefits of antibody therapy directed against cytokines such as IL-23 and IL-17. However, the exact (auto)antigen[s] targeted by T cells are not well known.

This short paper from Journal of Experimental Medicine suggests that a disintegrin and metalloprotease with thrombospondin motifs-like-5 protein (ADAMTSL5) expressed by melanocytes is a psoriasis-specific auto-antigen.

This study is continuation of earlier studies showing that (a) HLA-C*06:02 allele occurs in more than 60% of psoriatic patients, and (b) psoriatic lesion contains high frequency of Vα3S1⁺/Vβ13S1⁺ CD8 T cells. Now, using in vitro HLA transfection experiments the authors showed that Vα3S1⁺/Vβ13S1⁺ T hybridoma recognized HLA-C*06:02⁺melanocytes [but not keratinocytes or fibroblasts] in a HLA I-specific manner.

Next, using bioinformatics approach in combination with in vitro hybridoma activation assay (NF-κB-GFP readout), the authors identified ADAMTS-like protein 5 (ADAMTSL5) as a potential auto-antigen in psoriasis.

ADAMTSL5 was highyl expressed by both primary and cell line melanocytes (WM278).

Finally, the authors showed that ADAMTSL5 derived peptide stimulated psoriatic T cells but not T cells from healthy individuals.

In summary, this study showed that melanocyte-derived ADAMTSL5 represents auto-antigen in psoriasis. The authors claim that this is a first definitive report of showing psoriasis as a truly autoimmune diseases.

David Usharauli