Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome.

[omenn syndrome]

Hypomorphic RAG mutations , leading to limited V (D )J rearrangements , cause Omenn syndrome (OS ), a peculiar severe combined immunodeficiency associated with autoimmune -like manifestations . Whether B cells play a role in OS pathogenesis is so far unexplored . Here we report the detection of plasma cells in lymphoid organs of OS patients , in which circulating B cells are undetectable . Hypomorphic Rag 2 (R 229 Q ) knock-in mice , which recapitulate OS , revealed , beyond severe B cell developmental arrest , a normal or even enlarged compartment of immunoglobulin-secreting cells (ISC ). The size of this ISC compartment correlated with increased expression of Blimp 1 and Xbp 1 , and these ISC were sustained by elevated levels of T cell derived homeostatic and effector cytokines . The detection of high affinity pathogenic autoantibodies toward target organs indicated defaults in B cell selection and tolerance induction . We hypothesize that impaired B cell receptor (BCR ) editing and a serum B cell activating factor (BAFF ) abundance might contribute toward the development of a pathogenic B cell repertoire in hypomorphic Rag 2 (R 229 Q ) knock-in mice . BAFF-R blockade reduced serum levels of nucleic acid-specific autoantibodies and significantly ameliorated inflammatory tissue damage . These findings highlight a role for B cells in OS pathogenesis .

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22q11.2 deletion syndrome

adrenal incidentaloma

adrenomyeloneuropathy

alexander disease

aniridia

cadasil

canavan disease

congenital adrenal hyperplasia

epidermolysis bullosa simplex

erythropoietic protoporphyria

esophageal carcinoma

fabry disease

familial hypocalciuric hypercalcemia

hereditary cerebral hemorrhage with amyloidosis

inclusion body myositis

kabuki syndrome

omenn syndrome

phenylketonuria

primary effusion lymphoma

pyruvate dehydrogenase deficiency

scrub typhus

sneddon syndrome

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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