Innate Immune B Cells Gone Bad

Normal B lymphocytes can follow either of two functionally distinct pathways of development. The first is a classical germinal center T-dependent pathway in which diversification and maturation generate a delayed but almost unlimited high-affinity response to antigens. The second is a post-follicular marginal zone T-independent pathway, which provides the first line of innate defense against specific pathogens. Depending on the type of signaling,[1,2] B cells differentiate either into preactivated post-follicular marginal-zone B cells that reside in the marginal zone of the lymph node or into primed follicular mature B cells that reside in the lymph node follicle.[3,4]

When primed follicular mature B cells encounter a specific antigen, they undergo somatic hypermutation and class-switch recombination. These mature, class-switched, and hypermutated follicular B cells subsequently exit the germinal center either as memory B cells expressing immunoglobulin with high affinity for the antigen or, upon expansion and differentiation, as short-lived immunoglobulin-secreting plasma cells. In contrast, preactivated post-follicular marginal-zone B cells are specifically educated to respond rapidly to blood-borne T-independent antigens, and they provide a first line of innate defense against specific pathogens such as encapsulated bacteria.[5-8] Upon antigen stimulation, these preactivated post-follicular marginal-zone B cells expand and rapidly migrate into the blood either as plasma cells or as circulating IgM memory B cells.[7-8]

The cells that comprise these two distinct populations are the normal counterparts of important pathological entities in lymphoma-namely, germinal center–derived lymphomas that arise from follicular B cells, and post-follicular lymphomas that arise from marginal-zone B cells.[9] While lymphomas of germinal center origin are far more common, post-follicular lymphomas, which include splenic marginal zone lymphoma, nodal marginal zone lymphoma, and extranodal marginal zone lymphoma of the MALT (mucosa-associated lymphoid tissue) type, are relatively rare diseases; it is these latter that are the focus of the comprehensive review by Dr. Bertoni and colleagues.

In this review, the authors specifically highlight the association of this group of lymphomas with chronic infection and inflammation, emphasizing the role that the innate immune B cells play in the pathogenesis of these diseases. They review the association between chronic Helicobacter pylori infection and gastric MALT lymphoma, as well as the possible association of other infectious agents, including Borrelia, Chlamydophilia, and Campylobacter species, with MALT lymphomas at other sites. As discussed in this review, chronic inflammation induced by these infectious organisms results in chronic activation of the nuclear factor kappa B (NF-κB) pathway and proliferation of B cells. Removal of the infectious source with the use of antimicrobial therapy results in clinical remission-although a persistent B-cell clone can often still be identified by molecular techniques. In many cases, genetic alterations involving signaling molecules upstream of NF-κB are seen, and patients with these genetic alterations appear to have MALT lymphomas that are antigen-independent and nonresponsive to antibiotic therapy. What is not clear, however, is whether chronic antigen stimulation of B cells caused by persistent infection eventually leads to a genetic error in the B cells resulting in the known translocations seen in these diseases and rendering the malignant cell antigen-independent-or whether the genetic events in these patients occur independent of antigen exposure but result in an identical malignant phenotype. Regardless of the pathogenesis of the disease, the authors of the review provide a very helpful algorithm for managing patients based on the presence or absence of an identifiable infectious organism. They highlight the role of antibiotic therapy but also clarify the place of radiotherapy and combination treatment with chemotherapy and monoclonal antibodies such as rituximab (Rituxan).

As outlined in this review, marginal zone lymphomas of MALT type are indolent diseases that are relatively uncommon. A comprehensive understanding of the biology and genetics of these lymphomas is required to allow for a rational approach to their management. Dr .Bertoni and colleagues’ review of MALT lymphomas provides this by clearly summarizing the pathobiology of the disease, and also by providing clear guidance for the management of affected patients.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.