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. 2008 Sep 2;105(35):13009-14.
doi: 10.1073/pnas.0806874105. Epub 2008 Aug 28.

B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients

Irina Gavanescu  1 , Christophe Benoist, Diane Mathis
Affiliations

B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients

Irina Gavanescu et al. Proc Natl Acad Sci U S A. .

Abstract

Autoimmune regulator (Aire)-deficient mice and humans have circulating autoantibodies against a multitude of organs and multiorgan autoinflammatory infiltrates. It is not known to what extent autoantibodies or their source, B lymphocytes, are required for disease onset or progression. We show in this research that B cells must be present for Aire-deficient mice to develop fulminant infiltrates. We found no evidence that autoantibodies were directly pathogenic; rather, B cells appeared to play a critical early role in T cell priming or expansion. A therapeutic reagent directed against B cells, Rituximab, induced remission of the autoimmune disease in Aire-deficient mice, raising the hope of applying it to human patients with autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Blocking B cell differentiation in Aire−/− mice results in protection from autoimmunity. (A) Infiltrates in stomach and salivary gland of (B6 × 129) F2 Aire−/− (Left Images) and Aire−/−μMT−/− (Right Images) animals. Arrows denote lymphoid infiltrates (all 10× objective). (B) H&E-stained sections were scored for the severity of inflammation. The cumulative disease score was the sum of individual organ scores and was lower on average in Aire−/−μMT−/− (Left Column, n = 20) than in Aire−/− mice (Right Column, n = 36) (p = 0.0001). (C) Inflammation of the indicated organs was scored and compared in Aire−/−μMT−/− and Aire−/− mice.
Fig. 2.
Fig. 2.
B cells are responsible for lethal immunopathology in NOD.Aire−/− mice. (A) Cumulative disease scores (as defined in Fig. 1B) for Aire−/−μMT−/− (n = 7), Aire−/− (n = 9), μMT−/− (n = 4) and wild-type (n = 14) mice on the NOD background. Aire−/−μMT−/− compared with Aire−/− mice (p = 0.0013). (B) Infiltrates of prostates and epididimi of NOD.Aire−/− (Left Images) and NOD.Aire−/−μMT−/− mice (Right Images) (all 10× objective). Arrows indicate lymphoid infiltrates, severe in NOD.Aire−/− mice, but mild and diffuse in NOD.Aire−/−μMT−/− mice. (C) Inflammation scores were compared for individual organs in Aire−/−μMT−/− (n = 7) and Aire−/− (n = 9) mice on the NOD background. (D) Survival curves of Aire−/−μMT−/− (▴, n = 7) and Aire−/− (■, n = 11) mice on the NOD background.
Fig. 3.
Fig. 3.
Inflammation is abrogated by a complete block in B cell-differentiation. (A) Serum IgG levels of BALB/c wild-type (n = 8), Aire−/−Jh−/− (n = 13), Jh−/− (n = 7), and Aire−/− (n = 11) mice were assayed by ELISA and were compared with levels in the sera of NOD WT (n = 5), Aire−/−μMT−/− (n = 7), μMT−/− (n = 10), and Aire−/− mice (n = 6). (B) Sections of organs were stained by H&E, scored for the severity of inflammation, and accumulated for each mouse to yield an individual disease score. Average disease scores were compared for Aire−/−Jh−/− (n = 14), Aire−/− (n = 15), Jh−/− (n = 5), or wild-type (n = 7) mice on the BALB/c background; Aire−/−Jh−/− compared with Aire−/− mice (p = 0.00001).
Fig. 4.
Fig. 4.
No influence of maternally transferred Ig on inflammation in susceptible Aire−/− offspring. Organ inflammation due to Aire-deficiency was scored and summed in H&E-stained organ sections of 20-week-old (B6 × 129) F2 Aire−/− offspring of Aire−/− (n = 18) or Aire+/− mothers (n = 36).
Fig. 5.
Fig. 5.
Not Aire−/− serum, but Aire−/− T cells, transfer multiorgan inflammation. (A) Wild-type (B6 × 129) F2 mice were injected with Aire−/− or wild-type serum from 20-week-old (B6 × 129) F2 donors. Inflammation was assayed by H&E-staining of stomach sections from recipient mice. (B) Inflammation was assayed by H&E-staining of organ sections from Aire−/−Jh−/− recipient mice injected weekly for 8 consecutive weeks with Aire−/− serum (n = 6) or PBS (n = 5). (C) NOD.Rag−/− mice transferred with T cells from Aire−/− (n = 15) or Aire+/+ (n = 4) mice were assessed for the presence of inflammation by H&E-staining of organs affected in the donor NOD.Aire−/− mice.
Fig. 6.
Fig. 6.
B-cell-targeted immunotherapy ameliorates disease in Aire−KO NOD mice. (A) Schematic of Rituximab treatment. (B) Pancreatitis severity (null, 1 = mild infiltration, 2 = moderate infiltration with functional exocrine tissue, or 3 = severe infiltration with destruction of whole exocrine tissue) was scored on H&E sections of pancreata from Rituximab-treated and untreated mice. Transgene (tg)+ treated mice (n = 21) compared with: 1, tg+ untreated mice (n = 14, p = 0.013); 2, treated tg− mice plus untreated tg+ mice (n = 18, p = 0.03). (C) Immunoblot of pancreatic extract probed with serum from Rituximab-treated or untreated NOD.Aire−/− mice and with control reference sera; each lane shows autoantibody reactivity of individual mice. (D) Immunoblots of pancreas antigen detected at the end of the Rituximab-treatment by serum autoantibodies from treated or untreated NOD.Aire−/− mice.
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