Atypical memory B cells in human chronic infectious diseases: An interim report

Abstract

Immunological memory is a remarkable phenomenon in which survival of an initial infection by a pathogen leads to life-long protection from disease upon subsequent exposure to that same pathogen. For many infectious diseases, long-lived protective humoral immunity is induced after only a single infection in a process that depends on the generation of memory B cells (MBCs) and long-lived plasma cells. However, over the past decade it has become increasingly evident that many chronic human infectious diseases to which immunity is not readily established, including HIV-AIDS, malaria and TB, are associated with fundamental alterations in the composition and functionality of MBC compartments. A common feature of these diseases appears to be a large expansion of what have been termed exhausted B cells, tissue-like memory B cells or atypical memory B cells (aMBCs) that, for simplicity’s sake, we refer to here as aMBCs. It has been suggested that chronic immune activation and inflammation drive the expansion of aMBCs and that in some way aMBCs contribute to deficiencies in the acquisition of immunity in chronic infectious diseases. Although aMBCs are heterogeneous both within individuals and between diseases, they have several features in common including low expression of the cell surface markers that define classical MBCs in humans including CD21 and CD27 and high expression of genes not usually expressed by classical MBCs including T-bet, CD11c and a variety of inhibitory receptors, notably members of the FcRL family. Another distinguishing feature is their greatly diminished ability to be stimulated through their B cell receptors to proliferate, secrete cytokines or produce antibodies. In this review, we describe our current understanding of the phenotypic markers of aMBCs, their specificity in relation to the disease-causing pathogen, their functionality, the drivers of their expansion in chronic infections and their life span. We briefly summarize the features of aMBCs in healthy individuals and in autoimmune disease. We also comment on the possible relationship of human aMBCs and T-bet+, CD11c+ age/autoimmune-associated B cells, also a topic of this review volume.

Exhaustion may not be in the human B cell vocabulary, at least not in malaria

“…23 Consistent with this observation are the results from a number of cross-sectional and longitudinal studies that showed that the frequency of TLMBCs dropped in HIV-infected individuals in the months following antiretroviral therapy indicating that the virus was necessary for the renewal or maintenance of TLMBCs. 7,24 A recent Ig repertoire analysis showed that TLMBCs and classical MBCs shared clonal families of V H genes but that TLMBCs had lower levels of SHM and lower HIVneutralizing capacity as compared to resting classical MBCs suggesting a defect in affinity maturation. 25 Taken together these findings also suggested that classical MBCs and TLMBCs may differentiate from the same naive B cell pool.…”

“…[7][8][9] This subpopulation of MBCs, variously referred to as atypical MBCs, 10 tissue-like MBCs (TLMBCs) 11 or exhausted MBCs, 11 although not identical from infectious disease to infectious disease, have several features in common. is a large expansion of a subpopulation of MBCs that in healthy individuals represents only a small proportion of total B cells (approximately 3%-6%).…”

“…[7][8][9] However, at present it is not clear how atypical MBCs arise and whether they contribute to the inefficiency of antibody-mediated immunity in chronic infectious diseases. [7][8][9] However, at present it is not clear how atypical MBCs arise and whether they contribute to the inefficiency of antibody-mediated immunity in chronic infectious diseases.…”

“…is a large expansion of a subpopulation of MBCs that in healthy individuals represents only a small proportion of total B cells (approximately 3%-6%). [7][8][9] This subpopulation of MBCs, variously referred to as atypical MBCs, 10 tissue-like MBCs (TLMBCs) 11 or exhausted MBCs, 11 although not identical from infectious disease to infectious disease, have several features in common. They lack the classical marker for human MBCs, the TNF family member, CD27, and express low levels of the complement receptor, CD21, and show high expression of a variety of genes not expressed by classical MBCs including the T-cell transcription factor T-bet, that plays a critical role in T H1 fate commitment, the integrin CD11c generally expressed by dendritic cells (DCs).…”

“…Atypical MBCs are thought to expand in response to the continual antigen exposure and inflammation that are associated with chronic infectious diseases. [7][8][9] However, at present it is not clear how atypical MBCs arise and whether they contribute to the inefficiency of antibody-mediated immunity in chronic infectious diseases. In this review we briefly describe the discovery of human atypical MBCs and then focus on atypical MBCs that are expanded in children and adults living in malaria-endemic Africa.…”