The molecular basis of humoral autoimmunity: We have discovered that a carbohydrate esterase, hitherto never studied from the viewpoint of immune function, plays a major role in the pathogenesis of humoral autoimmune disorders. This gene regulates the function of key inhibitory receptors in B cells. We have obtained data from studies on knockout mice and analyses of the esterase gene in human subjects. Mutant mice exhibit attenuated signaling by inhibitory receptors, show exaggerated B cell activation, develop a break in B cell tolerance and develop humoral autoimmunity. All the exons of this gene have been re-sequenced in three cohorts of patients with autoimmunity, and in 190 controls. 8 patients with rheumatoid arthritis and lupus have been identified with point substitutions in this gene that prevent the protein it encodes from being secreted and completely compromise the catalytic activity of this enzyme.
B cell development and lineage commitment: An area of lymphocyte development that we study in considerable detail is the follicular versus marginal zone B lymphoid cell fate decision. BCR signal strength, Notch2, and NFkB p50 play major roles in this lineage commitment decision. In recent work we have genetically demonstrated synergism between Notch2 and NFkB1 during MZ B cell development, and shown that these proteins may cooperatively induce the transcription of common target genes.
The PKK/RIP4 kinase participates in stem cell to transit amplifying cell differentiation, and activates NFkB by a novel mechanism. A kinase that we cloned called PKC associated kinase (PKK) or RIP4, is required for normal skin development, and may be required in all adult stem cells. It activates NFkB by a unique IKKb dependent but IKKg independent mechanism. We continue to study this kinase by biochemical and genetic means.
Perisinusoidal B cells in the bone marrow mediate T-independent immune responses:We have described a unique habitat for follicular phenotype B cells in the bone marrow, in close apposition to bone marrow sinusoids. We now describe these cells as perisinusoidal B cells. Follicular phenotype B cells therefore have two distinct habitats. In lymphoid follicles they mediate T-B collaboration, but when they reside in their perisinusoidal habitat they respond to blood-borne pathogens in a T-independent manner. |
Papers & Publications:
1. Pillai S, Cariappa A, Moran ST. Marginal Zone B lymphocytes. Annu. Rev. Immunol. 2005, 23 161-96.
2. Cariappa A, Mazo IB, Chase C, Shi HN, Liu HY, Li Q, Rose H, Leung H, Cherayil BJ, Russell P, von Andrian U, Pillai S. Perisinusoidal B cells in the bone marrow mediate T independent IgM responses to blood- borne microbes. Immunity 2005, 23, 397-407.
3. Cariappa A, Liu HY, Chase C, Russell PS, Pillai S. Naïve recirculating B cells mature simultaneously in the spleen and bone marrow. Blood 2007 109, 2339-2345.
4. Moran ST, Cariappa A, Liu HY, Muir B, Sgroi DS, Boboila C, and Pillai S. Synergism between NFkB1 and Notch2 during the development of marginal zone B cells. J. Immunol. 2007 197, 195-200.
5. Cariappa A, Boboila C, Moran ST, Shi HN, Liu HY, Pillai S. The recirculating B cell pool contains two functionally distinct long-lived post-transitional follicular B cell populations. J. Immunol. 2007 in press. |
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