Levels of autoantibodies, unlike antibodies to all extrinsic antigen groups, fall following B cell depletion with Rituximab

Abstract

Many autoantibodies have variable-region sequences indicating their production in an affinity-matured antibody response involving germinal centers (GC). Plasma cells from GC can be long-lived, do not express CD20 and thus should not be depleted by a therapeutic monoclonal Ab against human CD20 -Rituximab. Nevertheless, autoantibody titers often fall following Rituximab treatment. To test if this reflects exclusive production by short-lived plasma cells in extrafollicular Ab responses, we monitored, after Rituximab treatment, levels of natural Ab and Ab against extrinsic antigens that do not induce productive GC. Eleven patients with active vasculitis and anti-proteinase-3 (PR3) Ab were assessed before and during 5 months after Rituximab therapy. Blood B cells were undetectable within 2 wk, and all patients achieved clinical remission. Levels of natural Ab -isohemagglutinins and anti-phosphorylcholine Ab -and Ab levels against thymus-independent and thymus-dependent extrinsic antigens were little affected. By contrast, 5 months after Rituximab, IgG autoantibody against PR3 had fallen to a median of 22% of pretreatment values. While the kinetics of this fall do not suggest an intrinsically short lifespan of autoantibody-producing cells, the data are consistent with Rituximab causing loss of sites within inflammatory tissues that selectively sustain autoantibody-producing cells.Supporting Information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2007/37557_s.pdf IntroductionRituximab is an IgG1 chimeric mouse/human monoclonal Ab directed against human CD20 that was developed for the treatment of lymphoma. Its administration causes profound depletion of B cells, which express CD20, from blood and tissues [1]. Rituximab has been used successfully to treat a number of autoimmune diseases. Significant falls in disease-associated IgG and IgM autoantibody levels are often seen [2-5] although this does not always happen [6, 7].Autoantibodies against the neutrophil serine protease, proteinase-3 (PR3), are encoded by Ig V region genes that have acquired somatic mutations [8]. These findings are consistent with the autoantibodies being produced by plasma cells whose precursors have undergone affinity maturation through hypermutation of their Ig V region genes and selection in germinal centers (GC) [9], although Ig V region mutations can be Certain types of Ag seem to induce only extrafollicular Ab responses, and many of the Ab-forming cells produced in these responses are short-lived [16,17]. These Ag include those based on pure polysaccharides and lipopolysaccharides that are not able to complete the CD4 T cell-dependent selection process required for plasma cells to differentiate from GC B cells [9]. In addition, B1 cells produce extrafollicular Ab responses, but probably do not form GC [18].B cell depletion by Rituximab provides the opportunity to investigate whether cells that maintain chronic Ab production after an extrafollicular response to Ag can be long-lived in the absence of B cell prec...

Local Renal Autoantibody Production in Lupus Nephritis

“…54 Despite this, immunosuppressive therapy does often reduce autoantibody titers, although it is interesting to note that after treatment with rituximab autoantibody levels often fall after clinical improvement has occurred (for example, see reference 55), and in many patients autoantibodies fall whereas those against previously experienced infection-related antigens do not. 56 The most likely explanation for these observations is that therapy, and in particular B cell depletion, is controlling inflammation, and that this in turn is reducing the inflammation-related PC survival niches in organs such as the kidney. The degree of fall in autoantibody titers may reflect the proportion of PCs in inflamed tissue, as those in the bone marrow should not be as influenced by a reduction in inflammation.…”

Parental caregivers of children with developmental disabilities mount a poor antibody response to pneumococcal vaccination

“…Cite this article as: Gallagher, S., Phillips, A.C., Drayson, M., & Carroll., D. (2009, invited article (Denham and Clarke, 2005;Sleeman et al, 2001). Further details of this assay are described elsewhere (Ferraro et al, 2008;Gallagher et al, 2008a;Lal et al, 2005).…”

Facultative role for T cells in extrafollicular Toll-like receptor-dependent autoreactive B-cell responses in vivo

“…Evidence for this comes from multiple mouse systems and can be inferred from the production of plasmablasts and short-lived autoantibody responses in humans (5,(7)(8)(9). It seems that a prominent requirement for systemic autoimmune EF responses is that the self-Ag contain a Toll-like receptor (TLR) ligand that is recognized by a B cell-intrinsic TLR.…”