Marginal zone B-cell dysfunction in ALPS

In this issue of Blood, Neven et al report that patients with autoimmune lymphoproliferative syndrome (ALPS) have poor production of anti-polysaccharide immunoglobulin (Ig) M antibodies and an elevated risk of pneumococcal sepsis and demonstrate that this is caused by infiltration and disorganization of the splenic marginal zone by the prototypical double-negative T cells.¹ 

ALPS is caused by genetic defects that prevent appropriate lymphocyte cell death.^2,3  Most patients harbor mutations in the FAS (TNFRSF6) death receptor gene and present with the predictable consequences of abnormal lymphocyte removal: chronic splenomegaly, lymphadenopathy, autoimmunity, and increased risk of lymphomas.^4,5 

Although under normal conditions these patients can handle perfectly well infections by viral, fungal, and bacterial agents, they seem to be exceedingly sensitive to spleen removal.

Sepsis by encapsulated bacteria is a well-known complication after splenectomy or during functional or congenital asplenia, but splenectomized ALPS patients have even higher complication rates compared with these populations.^1,6,7  In fact, the rate of invasive bacterial infections after splenectomy in ALPS reported here and in a recent publication by the National Institutes of Health ALPS group was as high as 30% and 50%, respectively.^1,6  Currently, postsplenectomy sepsis is the main cause of death in ALPS and not lymphoma development.^5,6 

In their article, Neven et al provide a plausible explanation for these findings and incriminate a cell population typically seen in ALPS: the TCRαβ⁺CD4⁻CD8⁻ T cells, also termed double-negative T cells (DN-Ts). They report that DN-Ts infiltrate and disorganize the splenic marginal zone (MZ) during periods of disease activity, leading to abnormal MZ B-cell function.

The splenic MZ is a specialized area at the interface between the circulation and the immune system, thought to be a prime site for the generation of first-line low-avidity IgM antibodies against blood-borne pathogens.⁸  These antibodies are produced by local MZ B cells, which in humans have a IgM^hiIgD^lowCD1c⁺CD21^hiCD27⁺ phenotype and seem to be particularly important for mounting T-cell independent anti-polysaccharide antigen responses.⁸  However, for their proper function, MZ B cells have to be correctly placed within the MZ, as antigens entering the spleen through the perifollicular zone are trapped by neutrophil extracellular trap-like structures emanating from unusual B-cell helper neutrophils inside the MZ.^8,9  The MZ B cells are then exposed to the trapped antigen and initiate antibody production locally, mostly IgM but also IgG or IgA.⁹ 

Neven et al demonstrate that the spleen MZ in ALPS patients with active disease is packed with DN-Ts, resulting in a paucity of MZ B cells in situ and in the peripheral blood. They go 1 step further by demonstrating that DN-Ts seem to be attracted to and retained within the MZ by the interaction between their α4 β7 integrin and a thick layer of MAdCAM-1 expressed by MZ stromal cells. This disruption of the normal MZ B-cell responses seems to result in a mild B-cell immunodeficiency that is aggravated by the removal of the spleen. These data could also explain findings of low numbers of circulating memory and MZ-like B cells and reduced serum IgM levels occasionally seen in ALPS patients with active disease.¹ 

Although not explored here, it is also plausible that the susceptibility of ALPS patients to pneumococcal sepsis after splenectomy may be further enhanced by DN-T infiltration into additional functional reserves of MZ B cells in humans, such as lymph nodes, tonsils, and intestinal Peyer’s patches.⁸ 

In addition to shedding light into the pathogenesis of the B-cell defects in ALPS, the data from Neven et al further strengthen the arguments against the removal of the spleen for the treatment of the autoimmune cytopenias seen in this disorder. Alternatives such as mycophenolate mofetil and sirolimus have recently been used with great success for disease control and are viable alternatives to the deadly splenectomy.¹⁰