Mechanisms of B cell autoimmunity in SLE

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is known to be associated with polyclonal B-cell hyperreactivity. The underlying causes of the diffuse B-cell over-reactivity are unclear, but potential candidates include (a) intrinsic hyper-reactivity leading to polyclonal B-cell activation with disturbed activation thresholds and ineffective negative selection; (b) lack of immunoregulatory functions; (c) secondary effects of an overactive inflammatory environment, such as overactive germinal center and ectopic follicular activity; and/or (d) disturbed cytokine production by non-B immune cells. These mechanisms are not mutually exclusive and may operate to varying extents and at varying times in SLE. Phenotypic and molecular studies as well as the results of recent clinical trials have begun to provide new insights to address these possibilities. Of importance, new information has made it possible to distinguish between the contribution played by abnormalities in central checkpoints that could lead to a pre-immune repertoire enriched in autoreactive B cells, on the one hand, and the possibility that autoimmunity arises in the periphery from somatic hypermutation and abnormal selection during T cell-dependent B-cell responses on the other. There is an intriguing possibility that apoptotic material bound to the surface of follicular dendritic cells positively selects autoreactive B cells that arise from non-autoreactive B-cell precursors as a result of somatic hypermutation and thereby promotes the peripheral emergence of autoimmunity.

Figure 1

Scheme of potential aberrations of T cell-dependent activation of B cells under the conditions of systemic lupus erythematosus. Intrinsic as well as extrinsic factors may lead to known B-cell hyperactivity as a result of enhanced germinal center reactions with defects in selection. As a net result, enhanced memory B cells and plasmacytosis could be explained and are consistent with abnormalities detectable in the blood of patients with active systemic lupus erythematosus.

Figure 2

Potential pathways involved in autoantibody generation in systemic lupus erythematosus (SLE). SHM, somatic hypermutation.

Figure 3

Comparative analysis of molecular germinal center signatures between antigen-experienced cells obtained from vaccinated controls versus systemic lupus erythematosus (SLE). V_H sequences of individual cells sorted as recombinant C-fragment of tetanus toxin (TT)-specific plasma cells (TT⁺ PCs) and TT-specific memory B cells (TT⁺ mBCs) were pooled from three healthy donors after tetanus booster [81] and plasma cells from one patient with SLE (SLE PCs) [14]. TT⁺ PCs and TT⁺ mBCs serve as effector cells generated as a result of prototypic T cell-dependent responses. (a) Mutation frequency. Each dot represents the value for one individual cell. (b) Ratios of replacement (R) to silent (S) mutations within complementarity-determining regions (CDRs) 1 and 2 and framework regions (FRs), respectively. (c) Frequency of mutations located within the two motifs RGYW and WRCY (R = purine, Y = pyrimidine, and W = adenine/thymine). (d) CDR3 length of individual B cells related to the underlying total number of mutations per sequence. Sequences of each cell type were divided into three categories according to their V_H region mutations (that is, 0 to 5 mutations, 6 to 10 mutations, and more than 10 mutations) and are plotted against their respective CDR3 lengths. Bar indicates median.

Figure 4

Characteristics of somatic hypermutation and generation of autoantibodies. AID, activation-induced cytidine deaminase; CDR, complementarity-determining region; Ig, immuonglobulin; RGYW, purine (R), guanine (G), pyrimidine (Y), adenine/thymine (W); S → R, silent-to-replacement; SHM, somatic hypermutation; WRCY, adenine/thymine (W), purine (R), cytosine (C), pyrimidine (Y).