Regulatory B cell

Regulatory B cells (Bregs or Breg cell) represent a small population of B cells which participates in immunomodulations and in suppression of immune responses. These cells regulate the immune system by different mechanisms. The main mechanism is a production of anti-inflammatory cytokine interleukin 10 (IL-10). The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions and in anti-tumor immunity.

History

In the 1970s it was noticed that Bregs could suppress immune reaction independently of antibody production.[1] In 1996 Janeway´s group observed an immunomodulation of experimental autoimmune encephalomyelitis (EAE) by B cells.[2] Similar results were shown in a model of chronic colitis one year later.[3] Then a role of Bregs was found in many mouse models of autoimmune diseases as rheumatoid arthritis[4] or systemic lupus erythematosus (SLE).[5]

Development and populations

Bregs can develop from different subsets of B cells. Whether Breg cells uniquely derive from a specific progenitor or originate within conventional B cell subsets is still an open question.[6] Bregs shared many markers with various B cells subsets due to their origin. Mouse Bregs were mainly CD5 and CD1d positive in model of EAE or after exposition of Leishmania major.[7][8] By contrast mouse Bregs in model of collagen-induced arthritis (CIA) were mainly CD21 and CD23 positive.[9] Breg were found in human, too. Markers of peripheral blood Bregs were molecules CD24 and CD38.[10] However, peripheral blood Bregs were mostly CD24 and CD27 positive after cultivation with anti-CD40 antibody and CpG bacterial DNA.[11] They were also positive for CD25, CD71 and PD-L1 after stimulation by CpG bacterial DNA and through TLR9.[12]

Mechanisms of action
Strukture of interleukin 10 (IL-10). Key player in Breg biology.

There are several mechanisms of Breg action. Nevertheless, the most examined mechanism is production of IL-10. IL-10 has strong anti-inflammatory effects.[13][14] and it inhibits or suppresses inflammatory reactions mediated by T cells, especially Th1 type immune reactions. This was shown for example in model EAE,[15] CIA[16] or contact hypersensitivity.[17] Likewise, regulatory B cell subsets have also been demonstrated to inhibit Th1 responses through IL-10 production during chronic infectious diseases such as visceral leishmaniasis.[18] Next suppressive Breg mechanism is production of transforming growth factor (TGF-β), another anti-inflammatory cytokine.[13] Role of Bregs producing TGF-β was found in mouse of models of SLE [5] and diabetes.[19] Another mechanism of Breg acting involves surface molecules, for example FasL[20] or PD-L1,[18][21] which cause death of target cells.

Activation

Resting B lymphocytes do not produce cytokines. After lipopolysaccharide (LPS) stimulation are produced TNFα, IL-1β, IL-10 and IL-6. This indicates that Breg must be stimulated to produce suppressive cytokines. There are two types of signals to activate Breg, namely signals generated by external pathogens and endogenous signals produced by the action of body cells. Structures characteristic of pathogenic microorganisms recognize the TLR receptors that trigger a signal cascade at the end of which is the production of effector cytokines. The main endogenous signal is the stimulation of the surface molecule CD40.[22]

Models of action

Autoimmune diseases

In autoimmune diseases, many models of Breg involvement are described in the suppression or alleviation of autoimmune pathology. The most well-known mechanism of action of Bregs is the production of anti-inflammatory cytokines, most IL-10. This mechanism was described in the EAE model,[15] but also in lupus erythematosus.[23] Another cytokine produced with an anti-inflammatory effect is TGF-β, which has a role in the suppression of T lymphocytes, for example in diabetes.[19] Not just cytokines can cause an anti-inflammatory state. There is also the second option to do it. There are also surface molecules (which may be FasL), which after binding to the target cell receptor, causes apoptosis. An increase in expression of this molecule has been described in the collagen-induced arthritis model.[24]

Tumors

In order to suppress immune responses, it is possible that cancerous proliferation uses Breg for its leakage from the immune system. Leukemia B cells spontaneously produce large amounts of IL-10.[25] Similarly, secretion of TNF-α B cells promotes the development of skin carcinoma.[26] However, the positive effect of Breg on the treatment of cancer is also described. In patients with metastatic cancer, those with a higher number of CD20 positive B lymphocytes in the lymph nodes are more likely to survive.[27]

Transplantation

The immunosuppressive properties of Breg play an essential role in allotransplants. It is necessary to cushion the immune response against the transplant and Breg can do it.[28] For other types of transplants, B cells can participate both in tolerance and more often in transplant rejection, depending on the origin of Breg subpopulations.

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