Spontaneously occurring neutralizing antibodies against granulocyte–macrophage colony‐stimulating factor in patients with autoimmune disease

Abstract

There is increasing evidence that spontaneous anticytokine autoantibodies are associated with chronic infections and autoimmune diseases. We report the sporadic occurrence in autoimmune diseases of such autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine involved in inflammation and the regulation of proliferation, differentiation and function of granulocytic and monocytic cell lineages. In 41 of 425 patients tested, we found low to moderate levels of autoantibodies binding to GM-CSF in serum or plasma. These were most prevalent in patients with myasthenia gravis (MG). However, neutralizing autoantibodies against GM-CSF were very rare, being found in only three patients. Two had autoimmune MG, one with thymoma (Patient A) and the other (Patient B) with 'seronegative' MG, i.e. without the antiacetylcholine receptor autoantibodies characteristic of most MG patients, and a third (Patient D) had multiple sclerosis. Only very limited amounts of Patient A and Patient D serum/plasma were available for analysis and therefore further studies were carried out on the more plentiful samples from Patient B. The anti-GM-CSF autoantibodies of Patient B were predominantly polyclonal immunoglobulin G and strongly neutralized recombinant human (rh) GM-CSF derived from different expression systems. They had similar immunological and immunochemical characteristics to anti-GM-CSF antibodies that developed in immunocompetent colorectal carcinoma patients following (rh)GM-CSF therapy. In serial samples from Patient B, the anti-GM-CSF autoantibodies were undetectable from diagnosis at age 8 years until at least age 13, but then developed spontaneously during (temporary) withdrawal of immunosuppressive treatment. Their neutralizing activity has persisted since their first detection at age 15 years 1 month, and was at its highest level recently at age 17 years 7 months. There was no obvious association with other autoimmune phenomena, nor were any haematological deficiencies overtly manifested, suggesting that any loss of GM-CSF function may have been compensated for by other cytokines.

High titer autoantibodies to GM-CSF in patients with AML, CML and MDS are associated with active disease

“…Antibodies to GM-CSF, while uncommon and of unknown significance, have been detected in patients with autoimmune diseases, 8 in neonatal cord blood, 9 and in 0.3% of healthy donors (HD). 10 Exogenous recombinant human GM-CSF can also elicit both humoral 11,12 and cellular 13 immune responses to GM-CSF when administrated as a single agent for hematopoietic recovery or as an adjuvant.…”

Clinical Utility of Anti- Granulocyte Macrophage-Colony Stimulating Factor Antibodies in Inflammatory Bowel Disease

“…Some other studies have shown that anti-GM-CSF Abs could be neutralizing antibodies or not (23)(24)(25).Indeed, it would also be interesting to evaluate GM-CSF bioactivity in parallel in order to determine if anti-GM-CSF Abs found in our cohort are neutralizing Abs.…”

Are neutralizing anti–GM-CSF autoantibodies present in all healthy persons?

“…In Uchida et al's study, 1 all healthy control sera tested were positive for anti-GM-CSF AA using an enzyme-linked immunosorbent assay. Although it is difficult to reconcile this observation with results from previous studies, [3][4][5]8 variations in assay design, format and serum factors may contribute to nonspecific reactivity and generate a false positive signal in the enzyme-linked immunosorbent assays. We believe that in demonstrating specificity, it is essential to show binding of GM-CSF to the F(abЈ) 2 fraction of anti-GM-CSF IgG and absence of binding of antibodies to other proteins (ie, non-GM-CSF).…”

“…Previously, high-titer neutralizing anti-GM-CSF AAs have been reported by Uchida et al (2004) 2 in sera from most patients with idiopathic pulmonary alveolar proteinosis (PAP) and by us in rare patients with myasthenia gravis, 3 but not in sera from healthy controls (HCs). Indeed, even non-neutralizing GM-CSF AA are relatively rare in sera from healthy controls [3][4][5] or autoimmune disease 5 and cancer patients. 6,7 Nevertheless, low-titer neutralizing anti-GM-CSF AAs have been found in human intravenous immunoglobulin (IVIg) products.…”

“…While the authors have shown that sera containing anti-GM-CSF AAs bind to both yeast-and Escherichia coli-derived recombinant GM-CSF, in our experience using E coli-derived GM-CSF, detection of anti-GM-CSF AAs in sera from cancer patients and healthy persons is very rare. 3,5,6 However, binding to yeast-derived recombinant GM-CSF and other yeast-expressed proteins (non-GM-CSF) may be problematic due to the presence of antibodies to yeast glycans. 9,10 The authors indicate that GM-CSF AAs are complexed with circulating GM-CSF and are present as immune complexes, but the approaches used for this appear to lack validation.…”