Importance of B cell co-stimulation in CD4+ T cell differentiation: X-linked agammaglobulinaemia, a human model

Martini, Hélène; Enright, Victoria; Perro, Mario; Workman, Sarita; Birmelin, Jennifer; Giorda, Ezio; Quinti, Isabella; Lougaris, Vassilios; Baronio, Manuela; Warnatz, Klaus; Grimbacher, Bodo

doi:10.1111/j.1365-2249.2011.04377.x

Cited by 39 publications

(43 citation statements)

References 49 publications

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“…It is also consistent with the findings that only one patient (who did not respond) had a detectable B cell clone -implicating the importance of reducing overall B cell numbers -and that the presence of T cell clones did not predict response to rituximab. Descriptions of abnormal T cell responses in patients who are congenitally without B cells further highlight the importance of the B to T cell stimulation, a concept that is relatively under-examined (Martini et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Platelet‐associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia

et al. 2012

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SummaryRituximab is widely used in autoimmune diseases including immune thrombocytopenia (ITP), although the mechanism of effect remains unclear. This study describes the effects of rituximab on platelet‐associated antibodies (PA‐APAs), B and T cell counts and clonality ( IGHV and TRG@ gene rearrangements), FCGR3A (FcγRIIIa) and FCGR2A (FcγRIIa) polymorphisms and correlation to anti‐CD40 ligand (CD40L) response. PA‐APA levels fell more frequently in responders (6/8) than in non‐responders (2/10: P = 0·08–0·15). Two responders had no PA‐APAs. Two non‐responders with a fall in PA‐APAs had very high CD8 levels. One non‐responder had a B cell clone, one responder and one non‐responder had a T cell clone. 15/16 patients had the same responses to rituximab and antiCD40L. Patients with FCGR3A V/V polymorphisms were more likely to respond to rituximab (P = 0·03). In summary, the fall in PA‐APAs in responders confirms the humoural effect of rituximab. Failure to respond in patients with very high CD8 levels, despite PA‐APA fall indicates a role for T cell‐mediated platelet/megakaryocyte destruction. Concordance of response to anti‐CD40L suggests autoantibody‐producing cells are under T cell control. Finally, the effect of FCGR polymorphisms on response confirms the importance of FCGR‐mediated depletion of B cells in autoimmunity. This has implications on the pathology of ITP as well as the immunological effect of B cell depletion.

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Section: Discussionmentioning

confidence: 99%

Platelet‐associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia

et al. 2012

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“…It is also plausible, however, that this Tfh defect reflects the absence of peripheral blood B cells because B cells are known to provide important trophic signals for this T-cell compartment. 54 Finally, this phenotype of the patients reported here is remarkable for the discordance between B-cell deficiency and antibody deficiency. Other examples of late-onset B-cell deficiency have been described in which the phenotype is more consistent with XLA.…”

Section: Nfkb2mentioning

confidence: 91%

Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100

Lee

Fulcher

Whittle

et al. 2014

Blood

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“…Detailed analysis of the T cell immunophenotype and TCR Vβ repertoire in 2 of the patients was similar to that seen in patients with mutations in BTK (ref. 21 and Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI71927DS1).…”

Section: Resultsmentioning

confidence: 99%

A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCRâ€“ B cells

Boisson¹,

Wang²,

Bosompem³

et al. 2013

J. Clin. Invest.

100

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IntroductionApproximately 85% of patients with early onset of infections, panhypogammaglobulinemia, and less than 2% CD19 + B cells in the peripheral circulation have X-linked agammaglobulinemia (1). This disorder is caused by mutations in Bruton tyrosine kinase (BTK) (2), a cytoplasmic tyrosine kinase that is activated by crosslinking of the pre-B cell and B cell antigen receptors (BCRs) (3). An additional 5%-7% of patients have rare autosomal recessive defects in components of the pre-BCR or BCR or in the downstream scaffold molecule B cell linker protein (BLNK) (4, 5). These genetic disorders all result in a block in B cell differentiation at the pro-B cell to pre-B cell transition, the stage at which the pre-B cell receptor is first expressed.We have recently described a group of 4 unrelated patients, 2 males and 2 females, with agammaglobulinemia and a very small number of B cells characterized by the lack of a BCR, but increased expression of CD19 (6). Bone marrow studies from these patients demonstrated a profound reduction in the number of CD19 + cells and a block in B cell differentiation at the common lymphoid precursor to pro-B cell stage of differentiation, a stage earlier than that seen in patients with BTK deficiency or mutations in components of the BCR signaling pathway.None of the 4 patients had a family history of immunodeficiency ( Figure 1A) or belonged to isolated populations or consanguineous families; therefore, we hypothesized that these

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Importance of B cell co-stimulation in CD4+ T cell differentiation: X-linked agammaglobulinaemia, a human model

Cited by 39 publications

References 49 publications

Platelet‐associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia

Platelet‐associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia

Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100

A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCRâ€“ B cells

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