Random recombination of antibody heavy-and light-chain genes results in a diverse B-cell receptor (BCR) repertoire including self-reactive BCRs. However, tolerance mechanisms that prevent the development of self-reactive B cells remain incompletely understood. The absence of the surrogate light chain, which assembles with antibody heavy chain forming a pre-BCR, leads to production of antinuclear antibodies (ANAs). Here we show that the naive follicular B-cell pool is enriched for cells expressing prototypic ANA heavy chains in these mice in a non-autoimmune background with a broad antibody repertoire. This results in the spontaneous formation of T-cell-dependent germinal centres that are enriched with B cells expressing prototypic ANA heavy chains. However, peripheral tolerance appears maintained by selection thresholds on cells entering the memory B-cell and plasma cell pools, as exemplified by the exclusion of cells expressing the intrinsically self-reactive V H 81X from both pools.

One of the principles behind vaccination, as shown by Edward Jenner in 1796, and host protection is immunological memory, and one of the cells central to this is the antigen-experienced memory B cell that responds rapidly upon re-exposure to the initiating antigen. Classically, memory B cells have been defined as progenies of germinal centre (GC) B cells expressing isotype-switched and substantially mutated B cell receptors (BCRs), that is, membrane-bound antibodies. However, it has become apparent over the last decade that this is not the only pathway to B cell memory. Here, we will discuss memory B cells in mice, as defined by (1) cell surface markers; (2) multiple layers; (3) formation in a T cell-dependent and either GC-dependent or GC-independent manner; (4) formation in a T cell-independent fashion. Lastly, we will touch upon memory B cells in; (5) mouse models of autoimmune diseases. AntibodiesAntibodies are assembled from antibody heavy (H) and light (L) chains (Fig. 1). The primary antibody repertoire is established early during B cell development through a process where V(D)J gene segments, encoding the variable region of the antibody H and L chains, are recombined [1]. In adults, this process takes place in the bone marrow, the primary organ for B cell development. At the same time, allelic exclusion of the antibody H and L chain loci is also established, which ensures expression of an antibody H and L chain encoded by only one of its respective alleles. The specificity of the primary antibody repertoire can be altered further through somatic hypermutation (SHM), a process that takes place in peripheral lymphoid organs and introduces mutations in the variable region of both H and L chains. This can result in an increase in the affinity of the antibody for its cognate antigen; termed affinity maturation.The variable domains of the antibody H and L chains determine its specificity and the constant region of the antibody H chain its effector function. Class switch recombination (CSR) is the mechanism by which a B cell changes isotype from expressing IgM and IgD to IgG, IgA or IgE, which alters its effector function while retaining the antigen specificity. As antibodies are differentially adapted to function in different compartments of the body, the isotype also contributes to their localization, for example, blood, extracellular fluids and mucosal tissues. B cell populationsImmature B cells express a B cell receptor (BCR) on their surface. This is, in fact, a membrane-bound antibody associated with the signalling molecules Iga/b. After completion of B cell development in the bone marrow, immature B cells migrate via the blood to secondary (peripheral) lymphoid organs, for example, spleen, where they differentiate into mature B cells. In adults, B cell development takes place in the bone marrow giving rise to B1 and B2 B cell subsets. These can be further subdivided into B1a and B1b, where the majority of B1a B cells stem from the fetal liver, and the B2 cells into follicular (FO) and marginal zo...

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Staphylococcus aureus-induced arthritis causes rapid joint destruction, often leading to disabling joint damage despite antibiotics. We have previously shown that interleukin-15 (IL-15) inhibition without antibiotics is beneficial in S. aureus-induced arthritis. We therefore hypothesized that the inhibition of IL-15, in combination with antibiotics, might represent a useful therapy that would reduce inflammation and joint destruction but preserve the host's ability to clear the infection. Female wild-type C57BL/6 mice were intravenously inoculated with the toxic shock syndrome toxin 1 (TSST-1)-producing LS-1 strain of S. aureus with 0.8 × 108 CFU S. aureus LS-1/mouse. Three days later, treatment consisting of cloxacillin, followed by flucloxacillin, together with either anti-IL-15 antibodies (aIL-15ab) or control antibodies, was started. Studied outcomes included survival, weight change, bacterial clearance, and joint damage. The addition of aIL-15ab to antibiotics in S. aureus-induced arthritis reduced synovitis and bone erosions compared to controls. The number of bone-resorbing osteoclasts in the joints was reduced, whereas cartilage destruction was not significantly altered. Importantly, the combination therapy did not adversely affect the clinical outcome of S. aureus-induced arthritis, such as survival or weight change, or compromise the host's ability to clear the infection. Since the clinical outcome of S. aureus-induced arthritis was not affected, the addition of aIL-15ab to antibiotics ought to be safe. Taken together, the combination of aIL-15ab and antibiotics is a beneficial, but not optimal, treatment of S. aureus-induced arthritis since it reduces synovitis and bone erosions but has a limited effect on cartilage destruction.

Background: Staphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis. Methods: C57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage. Results: Expansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host's ability to clear the infection. Conclusions: Pre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model.