Desminopathies may be described clinically and genetically as characterized by the presence of myofibrillar apparatus with protein aggregate and degenerative changes. Desmin protein inside muscle cells are misfolded and aggregated. The relationship between immune system and desminopathies may be inferred in a nutshell that desminopathy is a genetically driven disease with a significant and escalating immune mediated component. For elaborate information, internet may be logged-in.

you’re connecting clinical observations with pathomechanistic insights. Let’s break it down:

1. Background on desminopathy:

Desminopathies are myofibrillar myopathies caused by mutations in the desmin (DES) gene. Mutant desmin misfolds, aggregates, and disrupts intermediate filament networks in muscle fibers. This leads to structural fragility, mitochondrial dysfunction, impaired autophagy, and progressive muscle degeneration.

2. Evidence for immune involvement:

Chronic inflammation in muscle tissue: Biopsies often show inflammatory infiltrates, increased macrophage activation, and elevated proinflammatory cytokines (IL-6, TNF-α, IL-1β).

Upregulated stress and immune pathways: Proteotoxic stress and aggregate formation can activate innate immune sensors and inflammasomes.

Secondary autoimmunity: Muscle breakdown exposes intracellular antigens (like desmin aggregates, heat shock proteins, mitochondrial proteins) that could be recognized as “non-self.”

Clinical associations: Reports of allergy, cold sensitivity, and abnormal sweating in some patients may suggest systemic immune dysregulation, though this isn’t universal.

3. Possible immune-mediated progression mechanisms:

Innate immune activation: Misfolded desmin may act as a danger-associated molecular pattern (DAMP), triggering macrophages and dendritic cells.

Chronic cytokine signaling: Sustained IL-6, TNF-α, and IL-1β can exacerbate muscle catabolism and fibrosis.

Adaptive immune contribution: While less well established, presentation of mutant desmin peptides on MHC molecules might drive autoreactive T cells, leading to a myositis-like component in some patients.

Neuroimmune crosstalk: Sensitivity to cold/sweat dysregulation could reflect autonomic dysfunction with an inflammatory overlay.

4. Caveats:

Unlike classic autoimmune myopathies (e.g., dermatomyositis, polymyositis), desminopathy is fundamentally a protein-misfolding disease, not a primary autoimmune one.

Immune activation seems secondary — it may accelerate progression but is not the initiating cause.

More research is needed to determine whether immunomodulatory therapy could modify disease course (currently not standard).

✅ Summary:

The progression of desminopathy is not primarily immune-mediated, but immune mechanisms almost certainly contribute to disease worsening. Misfolded desmin acts as a chronic stressor that activates innate and possibly adaptive immune responses. Thus, inflammation likely acts as a disease amplifier rather than the root cause.

Absolutely—there’s a compelling case to explore immune-mediated mechanisms in the progression of desminopathy.

Desminopathy, a myofibrillar myopathy caused by mutations in the DES gene, is traditionally viewed through the lens of structural muscle damage. However, the presence of chronic inflammation, elevated proinflammatory interleukins (such as IL-1, IL-6, and TNF-α), and immune cell infiltration suggests that the immune system may play a more active role than previously thought.

Several clues support this hypothesis:

• Mutant desmin aggregates may act as damage-associated molecular patterns (DAMPs), triggering innate immune responses.

• Polyvalent allergies and hypersensitivity to cold/sweat hint at systemic immune dysregulation.

• Interleukin dysregulation, as seen in other autoimmune and inflammatory diseases, can perpetuate muscle injury through cytokine-mediated recruitment of inflammatory cells

If desminopathy involves a secondary immune-mediated cascade, it opens doors to novel therapeutic strategies—such as cytokine modulation, immune suppression, or targeted anti-inflammatory agents—alongside traditional genetic and regenerative approaches.

Dear Dipak Kumar Chattopadhyay, H.A Adewuyi and Afzal Ahmad, thank you very much for your detailed answers!

Thank you very much to dear Md Jakaria and H.A Adewuyi for recommending the question!

Yes, emerging evidence suggests that the progression of desminopathy may indeed involve immune-mediated mechanisms. While desminopathies are primarily caused by mutations in the DES gene encoding the intermediate filament protein desmin—leading to structural disintegration of the myofibrillar network and protein aggregation—the downstream effects appear to engage the immune system in complex ways.

Studies have shown that patients with desminopathy often exhibit chronic inflammation, elevated levels of proinflammatory cytokines such as IL-6 and IL-8, and signs of immune dysregulation. In particular, extended immunological profiling in patients with the T341P DES mutation revealed significant immunosuppression during disease progression, including reduced phagocytic and oxidative activity of monocytes and granulocytes, and altered immunoglobulin levels (e.g., decreased IgE, IgM, and IgG, but increased IgA). These findings suggest that the immune system is not merely reacting to muscle damage but may be actively contributing to disease pathology.

Moreover, the presence of polyvalent allergies and heightened sensitivity to cold and sweat in some patients points toward systemic immune hypersensitivity or dysregulation. These symptoms may reflect aberrant immune signaling or autonomic involvement, which could exacerbate muscle degeneration through sustained inflammatory responses or impaired tissue repair.

Dear Afzal Ahmad, thank you very much for your second answer!

Desminopathy progression appears to be at least partly immune-mediated. Mutant desmin disrupts the muscle cytoskeleton, leading to ongoing muscle fiber damage and release of danger signals. This triggers chronic inflammation with activation of immune cells and elevated proinflammatory cytokines, which further worsen muscle injury. The presence of polyvalent allergies, cold sensitivity, and sweating abnormalities in some patients also suggests heightened immune reactivity. Altogether, immune-mediated mechanisms likely contribute significantly to the progression of desminopathy alongside the primary structural defect.

Dear Muhammad Ishfaq, thank you very much for your reply!

My pleasure

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