mandag den 17. juni 2019

CTLA-4 induces IDO and SOCS3 drives degradation of IDO

The ME hypothesis "the metabolic trap" tell us that IDO function in immune cells may be compromised (1).

Dendritic cells (DCs) and T cells work together to maintain immune tolerance.

Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) downregulates the immune response. CTLA-4 binds to CD80 or CD86 on the surface of DCs. As a result DCs produce the tolerogenic tryptophan - catabolizing enzyme IDO (2):

Use links to figures:

Mutations in the gene CTLA4 have been associated with insulin-dependent diabetes mellitus, Graves disease, Hashimoto thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, and other autoimmune diseases (3).

Antibodies to thyreoperoxidase, to beta-adrenergic and muscarinic cholinergic receptors have been found in some ME patients (4).

Rheumatic heart disease is mediated by autoimmune reactions. Rheumatic fever and rheumatic heart disease lesions result from a complex network of several genes that control both the innate and adaptive immune responses after a S. pyogenes throat infection. An inflammatory process permeates the development of heart lesions with high production of inflammatory cytokines (IFNγ, TNFα, IL-17 and IL-23) and low numbers of cells producing IL-4, a regulatory cytokine of inflammation. Autoreactive CD4+ T cells infiltrate the heart tissue and trigger autoimmune reactions through molecular mimicry. A mutation in CTLA4 that affect the inhibitory function is found in some patients with rheumatic heart disease (5).

Autoimmunoreactive IgGs against cardic membrane proteins have been found in patients with POTS (6).

I wonder if some ME/POTS patients may have mutations in both IDO2 and CTLA4?

SOCS3 drives degradation of IDO

SOCS3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis (7, 8).

Use link to figure (7):

The transcription of SOCS3 has been found up-regulated in immune cells from ME patients (9).


1) Metabolic Traps in ME/CFS - Research Update by Dr. Robert Phair

2) Bourque JHawiger D: Immunomodulatory Bonds of the Partnership between Dendritic Cells and T Cells.  Crit Rev Immunol. 2018;38(5):379-401. doi: 10.1615/CritRevImmunol.2018026790.

3)  CTLA4 cytotoxic T-lymphocyte associated protein 4

4) Loebel et al: Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain Behav Immun. 2016 Feb;52:32-39. doi: 10.1016/j.bbi.2015.09.013. Epub 2015 Sep 21.

5) Guilherme et al: Rheumatic Heart Disease: Genes, Inflammation and Autoimmunity. Rheumatol Curr Res 2012, S4 DOI: 10.4172/2161-1149.S4-001

6) Wang et al: Autoimmunoreactive IgGs against cardiac lipid raft-associated proteins in patients with postural orthostatic tachycardia syndrome. Transl Res. 2013 Jul;162(1):34-44. doi: 10.1016/j.trsl.2013.03.002. Epub 2013 Apr 3.

7) Orabona et al. SOCS3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis. Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20828-33. doi: 10.1073/pnas.0810278105. Epub 2008 Dec 16.

8) Palotta et al: Proteasomal Degradation of Indoleamine 2,3-Dioxygenase in CD8 Dendritic Cells is Mediated by Suppressor of Cytokine Signaling 3 (SOCS3). Int J Tryptophan Res. 2010;3:91-7. Epub 2010 Jun 10.

9) Sweetman et al: Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Sweetman et al: Int J Immunopathol Pharmacol. 2019 Jan-Dec;33:2058738418820402. doi: 10.1177/2058738418820402.

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