Role of IgM Memory B Cells and Spleen Function in COVID-19

Abstract

IgM memory B cells, are a peculiar subset of memory B cells, which probably originates in the spleen and outside germinal centers and provide a rapid line of defence against mucosal infections. Their role in counteracting COVID-19 is still elusive but, recent evidence, mainly boosted by studies on spleen function/involvement in COVID-19, seems to support the notion that this subset of memory B cells could exert a protective role against this virus, along with other coronaviruses, particularly in the acute setting of the infection, as outlined by worst clinical outcomes observed in unvaccinated patients with impaired IgM B memory response and spleen function. Herein we critically summarise the current landscape of studies on IgM memory B cells, focusing on the clinical impact of their depletion, by comparing the COVID-19-related splenic dysfunction with other hypo- and asplenic conditions and by adding recent data on follow-up studies and postulate a mechanistic explanation for their reduced numbers. The early detection of an impaired IgM memory B cell response in patients with COVID-19 may contribute to their improved care through different strategies, such as through tailored vaccine strategies, prompt hospital admission and/or administration of anti-infective treatments, thus resulting in an better prognosis, although at present management algorithms are still unavailable. Moreover, further studies with longer follow-up are needed to assess the evolution of COVID-19-associated/exacerbated immune deficit.

Keywords: B cell; IgM memory B cell; SARS-CoV-2; hyposplenism; plasma cells.

Figure 1

The human splenic is depicted in (A); whereas its histologic appearance is shown in (B) The main part of the splenic tissue is the red pulp, whereas the white pulp represents less than 25 percent of the volume. Antigens reach the spleen only through the blood stream, via the splenic artery (not depicted for clarity), since the spleen lacks lymphatic vessels. The white pulp is made up of multiple lymph node-like regions, which are embedded in the red pulp, without a capsule. In (C) the ultrastructure of the white pulp is represented. The white pulp is surrounded by a layer of innate cells, like specialized macrophages subsets (Mp), making up the marginal zone (MZ) in mice and the perifollicular zone in humans. Bridges channels connecting the red and white pulp are not shown for clarity. Within the white pulp, different compartments can be identified, such as the B cell zone (BCZ) and the T cell zone (TCZ), which in humans is also called periarteriolar lymphoid sheath (PALS). In the BCL, germinal centers (GC) are found. They comprise a dark zone (DZ) and a light zone (LZ). In the DZ, B cells undergo cell division and somatic hypermutation; in the LZ, B cells with productive rearrangements in their B cell receptor, present antigens to T cells and differentiate into memory B cells (MBC) and plasma cells (PC), during germinal center reactions. MBC display migratory features to the extrafollicular areas of the spleen, as suggested by the arrow, and reach lymph nodes via the blood. After antigen encounter, MBC give rise to antibody-secreting PC. MBC can also re-enter the GC to acquire increased affinity for the antigen. PC preferentially migrate to the bone marrow, where they constitutively secrete antibodies with a precise specificity. GC- and T- cell independent reactions are also depicted. IgM memory cells (IgM-MBC) arise outside GC, mainly in the MZ. In humans, IgM-MBC are migratory; their trafficking to the gut epithelium is suggested by means of a dashed arrow. In the gut, IgM MBC give rise to IgA-secreting PC, which mediate mucosal immune responses against bacteria and viruses, through the production and delivery up to the intestinal lumen of secretory IgA (sIgA).