Short- and Long-Lived Autoantibody-Secreting Cells in Autoimmune Neurological Disorders

Abstract

As B cells differentiate into antibody-secreting cells (ASCs), short-lived plasmablasts (SLPBs) are produced by a primary extrafollicular response, followed by the generation of memory B cells and long-lived plasma cells (LLPCs) in germinal centers (GCs). Generation of IgG4 antibodies is T helper type 2 (Th2) and IL-4, -13, and -10-driven and can occur parallel to IgE, in response to chronic stimulation by allergens and helminths. Although IgG4 antibodies are non-crosslinking and have limited ability to mobilize complement and cellular cytotoxicity, when self-tolerance is lost, they can disrupt ligand-receptor binding and cause a wide range of autoimmune disorders including neurological autoimmunity. In myasthenia gravis with predominantly IgG4 autoantibodies against muscle-specific kinase (MuSK), it has been observed that one-time CD20⁺ B cell depletion with rituximab commonly leads to long-term remission and a marked reduction in autoantibody titer, pointing to a short-lived nature of autoantibody-secreting cells. This is also observed in other predominantly IgG4 autoantibody-mediated neurological disorders, such as chronic inflammatory demyelinating polyneuropathy and autoimmune encephalitis with autoantibodies against the Ranvier paranode and juxtaparanode, respectively, and extends beyond neurological autoimmunity as well. Although IgG1 autoantibody-mediated neurological disorders can also respond well to rituximab induction therapy in combination with an autoantibody titer drop, remission tends to be less long-lasting and cases where titers are refractory tend to occur more often than in IgG4 autoimmunity. Moreover, presence of GC-like structures in the thymus of myasthenic patients with predominantly IgG1 autoantibodies against the acetylcholine receptor and in ovarian teratomas of autoimmune encephalitis patients with predominantly IgG1 autoantibodies against the N-methyl-d-aspartate receptor (NMDAR) confers increased the ability to generate LLPCs. Here, we review available information on the short-and long-lived nature of ASCs in IgG1 and IgG4 autoantibody-mediated neurological disorders and highlight common mechanisms as well as differences, all of which can inform therapeutic strategies and personalized medical approaches.

Keywords: IgG4; autoantibody-mediated disorders; long-lived plasma cells; neurological autoimmunity; rituximab; short-lived.

Figure 1

Differentiation of B cells into short- and long-lived antibody-secreting cells. In the initial phase of the immune response to a T cell-dependent antigen, responding naïve B cells appear in the T cell zone of the lymph node (upper left), where their development and differentiation is facilitated by T cell-secreted cytokines. T helper type 2 (Th2) type cytokine secretion, such as IL-4, -10, and -13 favors the induction of an IgG4 response. B cells enter the extrafollicular pathway and undergo B cell receptor (BCR) activation by encountering antigens on follicular dendritic cells (FDCs), which they then present to T follicular helper (Tfh) cells through MHC-II. The extrafollicular pathway gives rise to (i) short-lived plasmablasts (SLPBs) that enter the periphery, and (ii) germinal center (GC)-independent memory B cells. In a second phase, activated B cells enter the GC dark zone, where they mutate (a process called somatic hypermutation) and clonally expand (therefore termed centroblasts). B cells cycle between the dark and the light zone (where they are termed centrocytes). The dynamic cycle of the GC allows centrocytes that entered the light zone to be chosen based on the affinity of their BCRs to the antigen. Low-affinity B cells that are not presenting antigen on their BCRs will eventually become apoptotic and die. B cells that do present the antigen receive help from Tfh through CD40L and IL21 survival signals. The end-products of the GC reaction are (i) memory B cells, and (ii) long-lived plasma cells (LLPCs). GC memory B cells will enter the periphery and re-enter the GC upon BCR stimulation. LLPCs exit the GC and find a survival niche, typically the bone marrow.

Figure 2

Human antibody isotype and class-switch recombination; diagram of the organization of the heavy chain gene locus. The constant genes are shown as squares and their width represents the relative gene size. Constant μ and δ (Cμ &Cδ) genes, preceded by the leader (L) and variable (V), diversity (D), or joining (J) gene regions, are expressed early in the B cell development. Recombination events (indicated as cutting sites) replace the Cμ and Cδ genes with other isotypes and subclasses (Cγ1-4, Cα1-2, and Cϵ) according to the depicted downstream order. IgG4 subclass antibodies can either be generated directly (left panel)—by IgM or IgD recombination and loss of the respective IGHC genes—or indirectly in two steps (right panel).