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Anti-cytokine autoantibodies: mechanistic insights and disease associations

Nature Reviews Immunology volume 24, pages 161–177 (2024)Cite this article

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Abstract

Anti-cytokine autoantibodies (ACAAs) are increasingly recognized as modulating disease severity in infection, inflammation and autoimmunity. By reducing or augmenting cytokine signalling pathways or by altering the half-life of cytokines in the circulation, ACAAs can be either pathogenic or disease ameliorating. The origins of ACAAs remain unclear. Here, we focus on the most common ACAAs in the context of disease groups with similar characteristics. We review the emerging genetic and environmental factors that are thought to drive their production. We also describe how the profiling of ACAAs should be considered for the early diagnosis, active monitoring, treatment or sub-phenotyping of diseases. Finally, we discuss how understanding the biology of naturally occurring ACAAs can guide therapeutic strategies.

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Fig. 1: Mechanisms responsible for breaking immune tolerance in the generation of anti-cytokine autoantibodies.
Fig. 2: Therapeutic approaches targeting anti-cytokine autoantibodies.

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Acknowledgements

This work was supported with funds from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, and funds from the Taiwan National Science and Technology Council awarded to A.C. (111-2314-B-002-173-MY3).

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Authors and Affiliations

  1. Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Aristine Cheng & Steven M. Holland

  2. Division of Infectious Diseases, Department of Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    Aristine Cheng

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  1. Aristine Cheng
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Correspondence to Steven M. Holland.

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Glossary

Artemis–DNA-PKCS complex

The Artemis nuclease and DNA-dependent protein kinase catalytic subunit (DNA-PKCS) are key components in non-homologous end joining (NHEJ), the major repair mechanism for double-strand DNA breaks. Artemis activation by DNA-PKCS resolves hairpin DNA ends formed during V(D)J recombination.

Autoimmune polyglandular syndrome type 1

(APS1, also known as APECED). A syndrome caused by mutation in the autoimmune regulator (AIRE) gene that is characterized by immune defects and autoimmunity, most commonly chronic mucocutaneous candidiasis and endocrinopathies such as chronic hypoparathyroidism and adrenal insufficiency.

Chronic granulomatous disease

A primary immunodeficiency wherein defects in NADPH oxidase (that can arise from mutations in five different genes) render phagocytes less effective at killing certain bacteria and fungi. Granulomas develop as a compensatory mechanism to wall off the infection in the skin and sinopulmonary and oral-gastrointestinal tracts.

Chronic mucocutaneous candidiasis

(CMC). Recurrent or persistent infections affecting the nails, skin and oral and genital mucosae caused by Candida spp., mainly Candida albicans. CMC is an infectious phenotype in patients with inherited or acquired T cell deficiency.

Common variable immunodeficiency

Describes various genetic abnormalities that result in a defect in the capability of immune cells to produce normal amounts of all types of antibodies, with the pathogenic consequence of recurrent sinopulmonary infections by viruses and encapsulated bacteria.

DiGeorge syndrome

A polygenic chromosome 22q11.2 deletion syndrome characterized by a triad of clinical features involving congenital cardiac defects, immune deficiencies secondary to aplasia or hypoplasia of the thymus, and hypocalcaemia owing to small or absent parathyroid glands.

Guillain–Barré syndrome

A rare neurological disorder resulting from post-infectious immune-mediated pathology affecting the peripheral nervous system, causing symptoms such as numbness, tingling and weakness that can progress to paralysis.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome

An extremely rare syndrome caused by mutation in the FOXP3 gene, which controls the production of regulatory T cells, that is characterized by watery diarrhoea, endocrinopathy (most commonly, insulin-dependent diabetes) and eczematous dermatitis in the first year of life.

Inborn errors of immunity

(IEIs). A group of nearly 500 inherited disorders, mostly owing to single-gene mutations, that impair or dysregulate immune function.

Post-herpetic neuralgia

Neuropathic pain that persists after cutaneous reactivation of the varicella zoster virus (commonly known as shingles) owing to damage to a peripheral nerve.

Pulmonary alveolar proteinosis

(PAP). A rare lung disease caused by surfactant accumulation in alveoli and impaired gas exchange.

Receptor editing

Ongoing recombination of the immunoglobulin light chain gene, leading to secondary rearrangements that can alter antigen specificity.

Severe combined immunodeficiency

A group of rare inherited disorders that results in combined deficiency or absence of T cell and B cell functions.

Somatic hypermutation

The stepwise incorporation of point mutations, that is, single-nucleotide substitutions, into the variable (V) region of rearranged immunoglobulin heavy and light chain genes. This occurs at a rate that is 106-fold higher than the spontaneous mutation rate in somatic cells and is the mechanism underpinning much of antibody diversity and affinity maturation.

V(D)J recombination

The reassembly of antigen receptor and antibody genes that occurs only in developing lymphocytes during the early stages of T cell and B cell maturation.

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Cheng, A., Holland, S.M. Anti-cytokine autoantibodies: mechanistic insights and disease associations. Nat Rev Immunol 24, 161–177 (2024). https://doi.org/10.1038/s41577-023-00933-2

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