Inflammatory Myopathies and Autoimmune Gluten-related Disorders: A Scoping Review of Pathophysiological Interconnections and Hypothesis

Abstract

Introduction: Anecdotal reports describe patients with concurrent idiopathic inflammatory myopathy (IIM) and celiac disease (CeD) in whom the introduction of a gluten-free diet led to dramatic improvement of myositis. We first systematically reviewed all peer-reviewed publications on concomitant IIM and duodenal biopsy-verified CeD. The collected evidence was suggestive of associations between myositis disease activity and gluten exposure in some patients with IIM-CeD.

Methods: To investigate possible explanations for the observations, an exploratory review of basic pathophysiological relationships between IIM and gluten-related disorders was performed using a combined strategy of systematic and non-systematic literature searches and forward and backward citation tracking.

Results: The investigations revealed close pathophysiological associations between IIM and the autoimmune gluten-related disorders CeD, dermatitis herpetiformis, and gluten ataxia. Common traits include shared genetic predisposition through HLA-DQ2.5/-DQ8, disease activity-associated autoantibodies, histopathological parallels with inflammatory cell infiltrates, and similarly distributed structural homologous transglutaminases (TGs). HLA-DQ2.5-restricted gluten-specific CD4+ T cells of a rare, uniform phenotype are reported in CeD and connective tissue disease. Expanded T-cell clones with identical phenotypes and CDR3β motifs indicate the presence of a continuous, antigen-driven T-cell response.

Conclusion: The investigations revealed that the main components involved in the adaptive immune response in the CeD gut may be present in HLA-DQ2.5+/-DQ8+ IIM muscle. The collected evidence supports the notion that in some genetically predisposed patients with IIM, gluten may act as an exogenous antigen driving myositis. Further Research/Clinical Implications: To test the above hypothesis, clinical trials combined with immunological studies are needed. Meanwhile, the inclusion of HLA-DQ typing may be justified, and subsequent small-intestinal biopsies in HLA-DQ2.5/8+ individuals with IIM.

Keywords: Idiopathic inflammatory myopathies; autoimmunity; environmental risk factors; extraintestinal manifestations.; gluten-related autoimmune disorders; pathophysiology.

Fig. (1)

Overview of the gluten-related disorders. Abbreviation: FDEIA: Food-dependent exercise-induced anaphylaxis.

Fig. (2)

Immunohistochemical analyses of TG2 in muscle Taken from Choi et al, 2004 (Fig. 3) [59]. Immunohistochemical analyses of TG2. Indirect immunofluorescence staining of TG2 was performed with frozen sections of DM, PM, DMD, and normal muscles. TG2 was strongly stained in the endomysial connective tissue and sarcolemma in IIMs. TG2 also decorates the degenerative muscle fibers in IIMs (arrow in DM indicates degenerative muscle fibers in perifascicular areas, and arrows in PM indicate non-necrotic muscle fiber and regenerative muscle fiber). Abbreviation: NL = Normal control. Antibody: polyclonal anti-human TGase 2, diluted 1:200, made in rabbit. License for re-use obtained from Karger Publishers.

Fig. (3)

Immunohistochemical analyses reveal co-localization of TG2 and TG1 in IBM muscle tissue From Choi et al, 2000, (Extracts from Fig. (3), f, r, t) [58]. Frozen sections from muscle of IBM patient. Both anti-TG1 and anti-TG2 strongly stained vacuoles along with β-amyloid (t), and anti-TG2 staining also showed strong reaction in the endomysial connective tissues and sarcolemma (r, t). (f) Anti-TG1 strongly stained vacuoles. (r) Anti-TG2 staining showed a strong reaction in endomysial connective tissues, sarcolemma, and vacuoles. (t) Colocalization of TG1, TG2, and β-amyloid proteins. The antibodies used in the figure were anti-TG1 in (r), anti-TG2 in (r, t), anti-β-A, and double immunostaining with β-amyloid in (t). Antibodies: polyclonal anti-human TGase 1 made in goat (26) diluted 1:200; polyclonal anti-human TGase 2 made in rabbit (10) diluted 1:200; and monoclonal anti-b-amyloid precursor protein and b-amyloid peptide (Zymed Laboratories Inc., San Francisco, CA) diluted 1:10 (27). Open access under Creative Commons CC-BY license.

Fig. (4)

Skeletal muscle from a coeliac patient with an endomysial TG2 pattern (J) and endomysial IgA deposits (K, green). Colocalization of IgA deposits with TG2 is indicated by yellow (L). From Korponay-Szabo et al (2004), (Excerpts from Fig. (2), (J-L)) [62]. Skeletal muscle from a celiac patient with an endomysial TG2 pattern (J) and endomysial IgA deposits (K, green). Co-localization of IgA deposits with TG2 is indicated by yellow (L). Antibody: monoclonal mouse antibodies against TG2 (CUB7402; NeoMarkers, Fremont, California, USA). License for re-use obtained from BMJ.