Introduction and rationale - Immunological memory is a hallmark of adaptive immunity. The humoral branch of immunological memory consists of memory conventional B cells, which are the precursors of long-lived plasma cells (ASC), which maintain serum Ab levels independent of antigenic stimuli in the bone marrow (BM) for months to years in the absence of antigen or cell division . Numerous changes are associated with ASC differentiation which distinguish them from memory B cells, including the loss of surface marker as B220 and the upregulation of CD43, CD138 and CD93. ASC express adhesion molecules and chemokine receptors, which could be involved in homing and selective survival in particular tissues or niches, mainly in the BM followed by spleen and inflamed sites . The biology of ASC remains enigmatic and is a matter of considerable debate. Of particular interest is whether ASC are long-lived and form a pool of memory plasma cells that is separate from the pool of memory B cells.
In principle, there are three competing concepts, which are not mutually exclusive, that might explain humoral memory . First, memory might arise by continued generation of short-lived plasma cells from memory B cells, a process that would be driven by persisting antigen.
Second, memory might arise by continued generation of ASC with a defined half-life from memory B cells, a process that would be activated by signals from cytokine receptors and Toll-like receptors.
Third, memory might arise by unconditional survival of plasma cells in survival niches in the bone marrow and inflamed tissues. Presently, the generation of memory B cell is becoming better understood, whereas the generation and maintenance of ASC are still poorly known, despite of being an imperative knowledge for improving vaccine development.
In the last few years, our lab has investigated the dynamic of B cell compartment generation in humoral memory response using fish venom and toxins as antigens. Thalassophryne nattereri fish envenomation is commonly reported in the Brazilian North and Northeast coast .
Recently we showed that venom induced the differentiation and maintenance of ASC with 5 different phenotypes, according to B220 and CD43 expression. Also, venom induces a chronic Th2-mediated inflammation with infiltration IL-17A-producing effector memory T cells (5,6).
Main objectives - We wish to determine the mechanism of differentiation and maintenance of ASC induced by the T. nattereri venom or Natterins (a family of major T. nattereri venom toxins with protease activity) by evaluating the mediators involved in the formation of survival niches in different compartments; to uncover how and when effector orcentral memory CD4+T cells help memory B cells; to analyze the requirement for the Toll-like receptors in the control of the magnitude of humoral immunity.
Specific aims: a) To understand how ASC are retained in specific compartments and to establish a model of differentiation between memory B cells and long-lived plasma cells; b) to explain how CD4 memory T cells and T follicular helper T could provide an enhanced helper response to B memory cells; c) to identify the requirements for TLR4, TLR2 and MyD88 for the magnitude of long-term humoral immunity and ASC maintenance.
Expected results : Prolonged survival of ASC in the BM has been implicated as a key component of long-term humoral immunity. Thus, the understanding of the extrinsic and intrinsic mechanisms responsible for the differentiation and survival of ASC open possibilities of pharmacological interruption of this program, which will likely be therapeutically useful to control chronic inflammatory diseases due to foreign invaders and to self antigens associated with tumors or cellular targets of autoimmunity.
References : 1. Manz et al Curr Opin Immunol 14 (2002) 517-521; 2. Chevrier et al. Proc Nat Acad Sci USA 106 (2009) 3895-3900; 3. Hiepe et al Nat Rev Rheumatol (2011) 7(3):170-8; 4. Fonseca and Lopes-Ferreira Ann Bras Dermatol (2000) 75: 435-443; 5. Grund et al Toxicon 2006; 48(5): 499-508; 6. Grund, Komegae, Lopes-Ferreira and Lima. Cytokine 2012. Submitted.