Potential role of anti-cytokine autoantibodies in the regulation of cytokine responses in infections and autoimmune diseases

Anti-cytokine autoantibodies are serum proteins that bind cytokines and specifically interfere with measurements and biological activities of the corresponding cytokines. Plasma, sera, and CSF were obtained from patients with multiple sclerosis (MS), aseptic meningitis (AM), stroke (ST), and polyneuropathy, Guillain Barré Syndrome (GBS). Blood samples and sera were obtained from patients with lower respiratory tract infection, and healthy controls. Detection of cytokines was performed by cell-release capturing (CRC)-ELISA. Anti-cytokine autoantibodies (Aabs) were detected by ELISA and the specificity was confirmed by western blot.

Increased levels of Aabs to interferon (IFN)-[gamma], tumour necrosis factor (TNF)-[alpha], interleukin (IL)-4, and IL-10 were detected in both cerebrospinal fluid (CSF) and plasma of MS and AM patients. Interestingly, in stroke (ST) patients Aabs were only detected in CSF only to IL-4 and IL- 10, but not to IFN-[gamma] or TNF-[alpha]. Furthermore, no significant Aab levels were registered in plasma against the 4 cytokines compared with healthy control subjects (HC). The latter group revealed very low Aab levels in plasma, although, no Aabs were detected in CSF. Patients with polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS) showed increased production of IFN-[gamma] and IL-4, while, low levels of Aabs to IFN-[gamma] and increased levels to IL-4 were associated with more severe disease. Numbers of cells secreting IFN-[gamma] in blood were augmented in GBS, in particular at the peak of clinical disease, and decreased during recovery. This decrease was associated with elevated serum concentrations of neutralizing IgG Aabs to IFN-[gamma].

In patients with lower respiratory tract infection, levels of IL-4 and IFN-[gamma] were inversely related to levels of their corresponding Aabs. A high amount of IFN-[gamma] was observed together with low anti-IFN-[gamma] Aab while decreased IL-4 levels were associated with increased Aabs to IL-4. Aab producing B-cells were cloned in an experimental model of bacterial meningitis. Screening of the clones with five different cytokines resulted in detection of Aab producing clones reactive with each cytokine. After repeated subcloning, monoclonal Aabs were selected and characterized for their specificity, isotype and affinity. Anti-cytokine Aabs, like anti-idiotype antibodies, probably have a physiological role in regulation of immune responses. The present studies, however, indicate that dysregulation by anti-cytokine Aabs may be pathogenetically involved in the induction and recovery from immune mediated diseases. Furthermore, induction of Aabs by cytokine therapy may be of clinical concern since their occurrence is often associated with the loss of response to treatment.

List of scientific papers

I. Elkarim RA, Mustafa M, Kivisakk P, Link H, Bakhiet M. (1998). Cytokine autoantibodies in multiple sclerosis, aseptic meningitis and stroke. European Journal of Clinical Investigation. 28:295-299.
https://pubmed.ncbi.nlm.nih.gov/9615907

II. Elkarim RA, Mustafa M, Link H, Bakhiet M, Ekerfelt C, Vrethem M, Ernerudh J. (1999). Induction of neutralizing autoantibodies to interferon-gamma in patients with polyneuropathy. Human Antibodies. 9:55-60.
https://pubmed.ncbi.nlm.nih.gov/10331186

III. Elkarim RA, Dahle C, Mustafa M, Press R, Zou LP, Ekerfelt C, Ernerudh J, Link H, Bakhiet M. (1998). Recovery from Guillain-Barre syndrome is associated with increased levels of neutralizing autoantibodies to interferon-gamma. Clinical Immunology & Immunopathology. 88:241-248.
https://pubmed.ncbi.nlm.nih.gov/9743610

IV. Elkarim R, Granert C, Lindquist L, Link H, Bakhiet M. (1999). Levels of gamma interferon and interleukin-4 are inversely related to the levels of their corresponding autoantibodies in patients with lower respiratory tract infection. Infection & Immunity. 67:3051-3054.
https://pubmed.ncbi.nlm.nih.gov/10338519

V. Bakhiet M, Elkarim R, Diab A, Zhu J, Lindquist L, Link H, Mustafa M. (1999). A novel mechanism for cytokine regulation: screening, selection, and characterization of anticytokine monoclonal and polyclonal autoantibodies. Journal of Interferon and Cytokine Research. 19:439-445.
https://pubmed.ncbi.nlm.nih.gov/10386855