We have challenged the long-standing paradigm that autoimmune diseases are merely a result of immune system hyperactivity. Instead, our research suggests that impaired immune signaling can lead to autoimmunity by failing to properly educate immune cells.
Caveolin-1 and B-Cell Dysfunction in Autoimmunity
- We discovered that Caveolin-1 regulates the plasma membrane nano-organization of B cells. Without Caveolin-1, B cell receptor (BCR) nanodomains fail to form, impairing B-cell activation. Proper BCR signaling is crucial for B-cell education, allowing developing B cells to distinguish self from non-self. In the absence of Caveolin-1, this process is disrupted, leading to autoimmunity (Minguet et al 2017).
- Our ongoing research is identifying novel signaling pathways in B cells and T cells that contribute to immunodeficiency and autoimmune disease (Minguet et al 2017; Schönle, Hartl et al 2016).
Genetic Mutations and Immunodeficiency
- We analyzed mutant forms of the kinase LCK, which phosphorylates the TCR. These mutations, found in immunodeficient patients, provide insights into how early TCR signaling defects contribute to immune disorders (Lui et al 2024; Keller et al 2023).
References
Lui VG, Hoenig M, Cabrera-Martinez B, Baxter RM, Garcia-Perez JE, Bailey O, Acharya A, Lundquist K, Capera J, Matusewicz P, Hartl FA, D’Abramo M, Alba J, Jacobsen EM, Niewolik D, Lorenz M, Pannicke U, Schulz AS, Debatin KM, Schamel WW, Minguet S, Gumbart JC, Dustin ML, Cambier JC, Schwarz K, Hsieh EWY (2024) A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation. J Exp Med 221(1):e20230927.
Keller B, Kfir-Erenfeld S, Matusewicz P, Hartl F, Lev A, Lee YN, Simon AJ, Stauber T, Elpeleg O, Somech R, Stepensky P, Minguet S, Schraven B, Warnatz K (2023) Combined Immunodeficiency Caused by a Novel Nonsense Mutation in LCK. J Clin Immunol 44(1):4.
Minguet S, Nyström A, Kiritsi D, Rizzi M (2022) Inborn errors of immunity and immunodeficiencies: Antibody-mediated pathology and autoimmunity as a consequence of impaired immune reactions.
Eur J Immunol
Minguet S*, Kläsener K, Schaffer AM, Fiala GJ, Osteso-Ibánez T, Raute K, Navarro-Lérida I, Hartl FA, Seidl M, Reth M, Del Pozo MA (2017) Caveolin-1-dependent nanoscale organization of the BCR regulates B cell tolerance. Nat Immunol 18(10):1150-1159. *corresponding author
Schönle A*, Hartl FA*, Mentzel J, Rauch KS, Wohlfeil SA, Nöltner T, Hechinger AK, Melchinger W, Fehrenbach K, Guadamillas MC, Prestipino A, Follo M, Prinz G, Ruess AK, Pfeifer D, Pozo MA, Schmitt-Graeff A, Duyster J, Blazar BR, Schachtrup K, Minguet S* and Zeiser R* (2016) Caveolin-1 regulates TCR signal strength and regulatory T cell differentiation into alloreactive T cells. Blood 15:1930-9. *Shared first/corresponding author.
