Naturally Occurring IgM Anti-Leukocyte Autoantibodies (IgM-ALA) Inhibit T Cell Activation and Chemotaxis

Abstract

The physiological relevance of naturally occurring IgM-ALA remains to be elucidated. These autoantibodies are present from birth and increase in diverse inflammatory states that are both infectious and noninfectious. Clinical observations showing significantly less acute allograft rejections in recipients having high IgM-ALA levels, led us to investigate whether IgM-ALA could have a functional role in attenuating T cell mediated inflammatory responses. In pursuit of this hypothesis, we did studies using IgM purified from the serum of normal individuals, patients with end stage renal disease, and HIV-1 infection. All preparations of IgM immunoprecipitated certain receptors e.g., CD3, CD4, CCR5, and CXCR4 from whole cell lysates but failed to immunoprecipitate IL-2R and HLA Ags. In physiological doses IgM down-regulated CD4, CD2 and CD86 but not CD8 and CD28, inhibited T cell proliferation, decreased production of certain proinflammatory cytokines e.g., TNF-α, IL-13 and IL-2, but not IFN- γ, IL-1β, GM-CSF, IL-6 and IL-8 and inhibited leukocyte chemotaxis. These inhibitory effects were more pronounced when using IgM from patients with high levels of IgM-ALA and these inhibitory effects were significantly reduced after using IgM preabsorbed with leukocytes. IgM-ALA binding to leukocytes was found to be highly specific, as <10% of IgM secreting B cell clones had IgM-ALA specificity with some clones having specificity for either T cells or monocytes. These findings support the concept that IgM-ALA provides an innate mechanism to regulate T cell mediated inflammatory responses.

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

“…ELISA was used to determine plasma levels of total and oxLDL‐specific antibodies (Ig, IgG, and IgM levels) as described before1, 29 and plasma IgM levels of anti‐CD3 and anti‐CD4 antibodies as described before 30. Plasma IL‐10 levels were determined by an ELISA kit (eBioscience) as recommended by the manufacturer.…”

Inhibition of HIV-1 Infectivity through an Innate Mechanism Involving Naturally Occurring IgM Anti-Leukocyte Autoantibodies

“…Many of the techniques including purification of IgM from serum, activation of PBL by alloantigens (MLR), anti-CD3 or PHA plus IL-2, chemotaxis assays, quantitation of cytokines in culture supernatants, immunoprecipitation techniques and Western blots to detect IgM binding to solubilized cell membrane receptors, and absorption of purified IgM with cell lines to remove IgM with anti-leukocyte reactivity have been described in detail in an accompanying manuscript (1). Similarly, the different cell lines used are also described in the accompanying manuscript.…”

“…The full repertoire of these Abs develops by early childhood and is present throughout life. IgM-ALA increases during various inflammatory and infectious disorders, including patients with end-stage renal disease (ESRD) and HIV-1 infections (1). We show that polyclonal IgM, purified from sera of normal patients and patients with ESRD and HIV-1 infections, has IgM-ALA that 1) binds to leukocyte receptors in a specific manner, even though they are polyreactive, 2) immunoprecipitates CD3, CD4, CCR5 and CXCR4 from whole cell lysates, 3) inhibits T cell activation as well as proliferation in response to alloantigens (MLR) or anti-CD3 (OKT3), 4) downregulates both extracellular and intracellular CD4 and CD2 receptors, and 5) inhibits chemokine binding to their receptors as well as chemokine-induced chemotaxis and receptor down-regulation.…”

“…Details on development, isolation, and characterization of these B cell clones are described in an accompanying manuscript (1). In these studies we compared IgM with and without IgM-ALA activity.…”

“…The PBL in this model are not preactivated with mitogens before viral infection and hence the previously described inhibitory effect of IgM on T cell activation can also play a role in controlling viral replication (1). In these studies normal IgM was used as it was difficult to obtain large amounts of sera from patients.…”