Dysregulation of germinal centres in autoimmune disease

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Abstract

In germinal centres, somatic hypermutation and B cell selection increase antibody affinity and specificity for the immunizing antigen, but the generation of autoreactive B cells is an inevitable by-product of this process. Here, we review the evidence that aberrant selection of these autoreactive B cells can arise from abnormalities in each of the germinal centre cellular constituents — B cells, T follicular helper cells, follicular dendritic cells and tingible body macrophages — or in the supply of antigen. As the progeny of germinal centre B cells includes long-lived plasma cells, selection of autoreactive B cells can propagate long-lived autoantibody responses and cause autoimmune diseases. Elucidation of crucial molecular signals in germinal centres has led to the identification of novel therapeutic targets.

Key Points

  • Long-lived high-affinity antibody responses are key components of adaptive immunity.

  • High-affinity antibodies are the products of somatic hypermutation and selection in specialized microenvironments of lymphoid tissues called germinal centres.

  • In this complex microenvironment, germinal centre B cells that are stimulated by antigen and dedicated helper T cells (T follicular helper cells) differentiate into memory B cells and long-lived plasma cells.

  • Many autoantibodies exhibit characteristics of germinal centre origin, indicating that defective selection of germinal centre B cells is instrumental in their formation.

  • Analysis of patients with autoimmune diseases, and mouse models of these diseases, reveal that autoantibodies can result from abnormalities in antigen availability, T cell help or the threshold at which B cells respond to these stimuli in germinal centres.

  • Qualitative and quantitative variation in antigen availability and T cell help determine germinal centre longevity and autoantibody formation.

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Figure 1: Germinal centre cell types and events.
Figure 2: Molecular basis of germinal centre events and potential therapeutic intervention.

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Acknowledgements

C.G.V. and M.C.C. are funded by the Australian National Health and Medical Research Council, and C.G.V. is a recipient of a Viertel Senior Medical Research Fellowship.

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Correspondence to Carola G. Vinuesa.

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Glossary

Autoantibody

Antibody directed against an organisms own tissues.

Antinuclear antibodies

(ANAs). Heterogeneous autoantibodies against one or more antigens present in the nucleus, including chromatin, nucleosomes and ribonuclear proteins. ANAs are found in association with many different autoimmune diseases.

Centroblast

A proliferating germinal centre B cell with rearranged variable-region immunoglobulin genes that are undergoing somatic hypermutation.

Somatic hypermutation

(SHM). A programmed process of mutation targeting the variable regions of immunoglobulin genes that allows the selection of B cells that express immunoglobulin receptors with highest affinity for foreign antigens.

Immunoglobulin class switching

(also known as class switch recombination (CSR)). A process that changes the constant region portion of the antibody heavy chain from one class (that is, IgM, IgD, IgG or IgA) to another, enabling the antibody to perform different effector functions and leaving the variable region of the heavy chain – and thus antigen specificity – unchanged.

T follicular helper (TFH) cell

A type of helper T cell that differentiates on Bcl-6 expression, localizes to follicles owing to high expression of CXCR5 and CXCR4 and provides CD40L- and IL-21-mediated selection and survival signals to germinal centre B cells.

Centrocyte

The non-dividing progeny of a centroblast. These cells need to be selected on the basis of their affinity for antigen, following interaction with immune complexes that are associated with follicular dendritic cells, and their ability to elicit help from TFH cells.

Complementarity-determining regions

A short amino acid sequence found in the variable domains of antigen receptor proteins that complements an antigen and therefore provides the receptor with its specificity for that particular antigen.

Rheumatoid factor

An autoantibody against the Fc portion of IgG present at high levels in 80% of patients with rheumatoid arthritis and almost 100% of patients with Sjgrens syndrome. Rheumatoid factor and IgG join to form immune complexes, which contribute to disease.

MRL/lpr mice

A mouse strain that spontaneously develops glomerulonephritis and other symptoms of SLE. The lpr mutation causes a defect in CD95, preventing the apoptosis of activated lymphocytes; the MRL strain contributes disease-associated mutations that have yet to be identified.

Systemic lupus erythematosus

(SLE). A chronic autoimmune disease in which autoantibodies against double-stranded DNA contribute to inflammation and tissue damage, usually affecting the heart, joints, skin, lungs, blood vessels, liver, kidneys and nervous system.

NZB mice

An inbred autoimmunity-prone mouse strain that spontaneously develops an SLE-like disease, characterized by autoimmune (Coombs test-positive) haemolytic anaemia and glomerulonephritis. F1 hybrids with NZW (derived from the same outbred stock as NZB) develop a disease that closely resembles human SLE, characterized by high titres of autoantibodies and glomerulonephritis.

K/BxN mice

Mice that express both the KRN T cell receptor transgene and the NOD-derived MHC class II molecule I-Ag7 and develop severe inflammatory arthritis as a result of the specificity of the transgenic TCR for a peptide derived from the ubiquitously expressed self protein glucose-6-phosphate isomerase in the context of I-Ag7.

Ectopic lymphoid structures

(Also known as tertiary lymphoid organs). Organized lymphocytic aggregates that form at sites of chronic inflammation. Typically, B cell- and T cell-rich zones are segregated, and dendritic cells (DCs), germinal centres with follicular DC (FDC) networks and specialized endothelia are present.

9G4 B cells

B cells that make autoreactive antibodies that target the I/i blood group antigen and related determinants present in CD45 and other self glycoproteins. High titres of these antibodies are found in patients with active SLE and contribute a significant fraction of native double-stranded DNA-specific antibodies in these patients.

BXSB/Yaa mice

An autoimmunity-prone strain of mouse (BXSB) with the Y chromosome-linked autoimmune accelerator (Yaa) mutation, which is a duplication and translocation of a segment of the X chromosome that contains several genes, including Toll-like receptor 7 (Tlr7), to the Y chromosome. Male BXSB mice develop a severe form of SLE with a much higher incidence than their female counterparts.

Anergy

A state of non-responsiveness to antigen. Anergic B or T cells cannot respond to their cognate antigens under optimal conditions of stimulation.

Bz423

A pro-apoptotic 1,4-benzodiazepine that induces cell cycle arrest and apoptosis by promoting the formation of superoxide in the mitochondrial respiratory chain, which leads to the activation of pro-apoptotic proteins. It has been used in mouse models of SLE in which it seems to selectively target autoreactive lymphocytes.

Erythroblastic islands

Specialized bone marrow niches comprising erythroblasts surrounding a central macrophage where erythroid precursors proliferate, differentiate and enucleate.

Tingible body macrophages

(TBMs). A type of macrophage that is specifically located in GCs. TBMs are found in close proximity to follicular dendritic cells, and engulf lymphocytes that undergo apoptosis in the GCs. TBMs can also have an inhibitory effect on the B cell-mediated stimulation of T cell responses when added to ex vivo co-cultures.

MRL/gld

Mice that have a naturally occurring mutation in CD95 ligand that causes a generalized lymphoproliferative disease, similar to that of MRL/lpr mice.

BXD2 mice

One of several recombinant inbred mouse strains generated by inbreeding the intercross progeny of C57BL/6J and DBA/2J mice for more than 20 generations. The BXD2 phenotype includes spontaneous erosive arthritis, circulating immune complexes and glomerulonephritis.

Double-stranded DNA-specific antibodies

A subset of antinuclear antibodies specific for double-stranded DNA that are expressed in 4050% of patients with SLE and are seldom found in association with other autoimmune diseases.

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Vinuesa, C., Sanz, I. & Cook, M. Dysregulation of germinal centres in autoimmune disease. Nat Rev Immunol 9, 845–857 (2009) doi:10.1038/nri2637

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