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.

Introduction

Throughout recorded history one of the most feared causes of death was infectious diseases that in epidemic proportions have the power to decimate entire societies. From the writings of the historian Thucydides describing the plague of Athens in 430 BCE it is clear that it was appreciated even at that time that individuals who survive an infection are subsequently protected from future infections. Thucydides wrote: “Yet it was with those who had recovered from the disease that the sick and the dying found most compassion. These had no fear for themselves, for the same man was never attacked twice – never at least fatally” [1]. We now understand that Thucydides was describing the acquisition and function of immunological memory and indeed, for most infectious diseases, those that survive are immune to disease upon re-exposure to the same pathogens. However, not all pathogens induce protective immunity, and by definition, cause chronic infectious diseases including HIV-AIDS, malaria, TB and hepatitis. Although these are complex diseases and we do not in any case fully understand the cellular or molecular basis of the failure to rapidly develop immunologic memory, it is now clear that many chronic infections are associated with fundamental differences in the composition of the memory B cell (MBC) compartment. It has been postulated that such alterations in immune cell populations may contribute to the poor acquisition of immunity to such diseases. In this review we focus on a phenomena that appears to be in common between HIV, Plasmodium falciparum, Mycobacterium tuberculosis (Mtb) and Hepatitis C infections, namely, the large expansion of a subpopulation of B cells (up to 50% of all circulating B cells) that normally represents only a small percent (approximately 3–5%) of peripheral blood B cells in healthy individuals. These B cells have several characteristics of MBCs and are referred to variously as exhausted MBCs, tissue-like memory B cells in HIV-AIDS or atypical MBCs (aMBCs) in malaria. Here we refer to these cells as aMBCs for simplicity’s sake. It is becoming increasingly clear that aMBCs are not a homogenous population of B cells, but rather show significant heterogeneity both within an individual for a given disease as well as between different chronic infections. It is possible that aMBCs contain a variety of subsets with specialized functions that differentially expand under different conditions. HIV-AIDS, malaria and TB, that together cause more than five million deaths a year, continue to elude conventional vaccine development. Thus, it is a public health priority to understand the cellular and molecular basis of the function of aMBCs and the drivers of their differentiation, to improve our chances of developing effective, life-saving vaccines for these deadly diseases.

We now understand that MBCs develop in secondary lymphoid organs such as the spleen and lymph nodes [2], [3], [4], [5] (Fig. 1). Naïve B cells encounter antigens in the follicles in many cases as immune complexes or complement fixed antigens bound to Fc receptors, complement receptors or scavenger receptors on the surface of dendritic cells (DC). B cells engage antigen through their B cell receptors (BCRs) that initiates signaling cascades that induce the transcription of a variety of genes associated with B cell activation. The BCR bound antigen is then internalized into specialized compartments where the antigen is processed and then presented on MHC class II molecules on the B cell surface. At the B-T cell border of the follicle, B cells engage CD4⁺ T cells that have been activated by antigen processed and presented by DCs to initiate differentiation toward T follicular helper (Tfh) cells. If the quality of the T-B interaction is high, the T cells further differentiate into Tfh cells and the Tfh cells and B cells proliferate and enter germinal centers (GCs). If the interaction is in some way inadequate, B cells are not induced to enter the GCs but rather proliferate and differentiate into short-lived antibody secreting plasma cells (PCs) and what have been termed GC-independent MBCs [3]. B cells that enter the GC first enter the GC dark zone (DZ) where they clonally expand by proliferation and undergo class switching and somatic hypermutation (SHM). B cells exit the DZ to enter the light zone (LZ) where B cells with the highest affinity for antigen are ultimately selected by the Tfh cells to differentiate into long-lived MBCs and PCs, in a process that depends on the ability of B cells to capture antigen from follicular DC (fDC) and present it to Tfh cells.

In this review we describe the characteristics of aMBCs, the role of pathogen-derived antigens in their expansion, the functionality of these cells, their longevity and cellular and molecular mechanisms that drive their differentiation. We briefly comment on aMBCs in autoimmune disease and in healthy individuals and the similarities between aMBCs and age-associated B cells (ABCs) in mouse models. Lastly, we propose a model for the expansion of aMBCs during chronic infectious diseases in the framework of the emerging view of the normal development of B cell memory.