The chronically inflamed central nervous system provides niches for long-lived plasma cells

Abstract

Although oligoclonal bands in the cerebrospinal fluid have been a hallmark of multiple sclerosis diagnosis for over three decades, the role of antibody-secreting cells in multiple sclerosis remains unclear. T and B cells are critical for multiple sclerosis pathogenesis, but increasing evidence suggests that plasma cells also contribute, through secretion of autoantibodies. Long-lived plasma cells are known to drive various chronic inflammatory conditions as e.g. systemic lupus erythematosus, however, to what extent they are present in autoimmune central nervous system inflammation has not yet been investigated. In brain biopsies from multiple sclerosis patients and other neurological diseases, we could detect non-proliferating plasma cells (CD138 + Ki67 − ) in the parenchyma. Based on this finding, we hypothesized that long-lived plasma cells can persist in the central nervous system (CNS). In order to test this hypothesis, we adapted the multiple sclerosis mouse model experimental autoimmune encephalomyelitis to generate a B cell memory response. Plasma cells were found in the meninges and the parenchyma of the inflamed spinal cord, surrounded by tissue areas resembling survival niches for these cells, characterized by an up-regulation of chemokines (CXCL12), adhesion molecules (VCAM-1) and survival factors (APRIL and BAFF). In order to determine the lifetime of plasma cells in the chronically inflamed CNS, we labeled the DNA of proliferating cells with 5-ethynyl-2′-deoxyuridine (EdU). Up to five weeks later, we could detect EdU + long-lived plasma cells in the murine CNS. To our knowledge, this is the first study describing non-proliferating plasma cells directly in the target tissue of a chronic inflammation in humans, as well as the first evidence demonstrating the ability of plasma cells to persist in the CNS, and the ability of the chronically inflamed CNS tissue to promote this persistence. Hence, our results suggest that the CNS provides survival niches for long-lived plasma cells, similar to the niches found in other organs. Targeting these cells in the CNS offers new perspectives for treatment of chronic autoimmune neuroinflammatory diseases, especially in patients who do not respond to conventional therapies.

Immunological memories of the bone marrow

“…Similarly, they can survive for decades in the human gut,19 and it has been discussed that long‐lived mucosal plasma cells may play a role in maintaining the mucosal microbiota 20. Apparently, plasma cells can also persist in inflamed tissue, as in the inflamed kidneys of NZB/W mice21, 22 or the inflamed central nervous system of mice with experimental autoimmune encephalomyelitis 23. During acute inflammation in the inflamed tissue, the persistence of plasma cells, in particular those secreting antibodies specific for pathogens driving the inflammation, would provide local protection.…”

“…20 Apparently, plasma cells can also persist in inflamed tissue, as in the inflamed kidneys of NZB/W mice 21,22 or the inflamed central nervous system of mice with experimental autoimmune encephalomyelitis. 23 During acute inflammation in the inflamed tissue, the persistence of plasma cells, in particular those secreting antibodies specific for pathogens driving the inflammation, would provide local protection. In chronically inflamed tissues longlived plasma cells secreting autoantibodies might themselves drive the inflammation.…”

Anti-CD20–mediated B-cell depletion in autoimmune diseases: successes, failures and future perspectives

“…Besides the spleen, autoreactive PCs may infiltrate target organs such as kidneys, 23 the central nervous system, 24 synovium, 25 or salivary glands. 26 We also observed kidney PCs with a long-lived program that resisted immunosuppressive therapy in lupus nephritis (E. Crickx et al, unpublished data, 2020).…”

Lymphoid Aggregates in the CNS of Progressive Multiple Sclerosis Patients Lack Regulatory T Cells

“…Accordingly, the total absence of T FR s and the succeeding unrestrained T-cell help to low-affinity, poly-reactive or even autoreactive B cells must lead to overshooting GC reactions and the occurrence of CNS-specific autoantibodies in MS patients. In line, PCs have been detected scattered in the CNS parenchyma of remitting-relapsing and secondary progressive MS patients, but in SPMS patients predominantly at the periphery of B-cell follicles /eLFs (31,43).…”