Defect of regulatory T cells in Omenn syndrome leads to a breakdown of peripheral tolerance and autoimmune complications

Omenn syndrome (OS) is an autosomal-recessive disorder characterized by severe immunodeficiency (SCID) and T-cell-mediated autoimmunity. Omenn syndrome is due to RAG enzyme defects.

Severe Combined Immunodeficiency (SCID) (click to enlarge the image).

The Omenn syndrome is caused by hypomorphic mutations in recombination-activating genes that hamper the process of Variable (V) Diversity (D) Joining (J) recombination (recombinase genes RAG-1 and RAG-2), leading to the generation of autoreactive T cells.

Receptor editing reactivates RAG-1 and RAG-2 when a high affinity self-antigen is recognized by a B cell receptor (BCR).

The expression of autoimmune regulator, a key factor governing central tolerance, is markedly reduced.

The researchers analyzed forkhead box protein P3 (FOXP3) expression in peripheral blood T cells and lymphoid organs in OS. They also tested the suppressive activity of CD4(+) CD25(high) peripheral blood T cells (T regs).

CD4(+)CD25(high)T cells (T regs) failed to suppress proliferation of D4(+) responder T cells. Immunohistochemical analysis of FOXP3 expression in lymph nodes and thymus showed a severe reduction of this cell subset.

A defect of regulatory T cells in OS leads to a breakdown of peripheral tolerance, which then leads to autoimmune complications.

Regulatory T cells - 5 groups have been described as of year 2010:

- CD4+CD25+ regulatory T cells ("classic" T regs)
- TR1 cells, CD4 cells that secrete IL-10
- Th3 cells, a subset of CD4+ cells that secrete TGF-b
- CD8+ suppressor T cells
- γ/δ T cells

Regulatory T cells - 5 groups have been described as of year 2010 (click to enlarge the image).

Severe combined immunodeficiency (SCID) - 4 groups according to T/B/NK cells (click to enlarge the image).

In SCID, the younger the age of the patient at the time of transplantation, the better the prognosis. There is a 95% survival rate in an infant who undergoes a transplant before 3 months of age. After six months, the survival rate decreases dramatically, to 50%.

Conditions with elevated IgE

Atopic dermatitis, Asthma, ABPA, and allergic fungal sinusitis
Infections (parasites, HIV, TB, EBV, and CMV)
Malignancy (IgE myeloma and lymphoma)
Churg-Strauss syndrome
Kimura’s disease, painless, unilateral cervical lymphadenopathy or subcutaneous masses in the head or neck region

Immunodeficiency diseases with elevated IgE

Hyper IgE syndrome (HIES)
Wiskott-Aldrich syndrome (WAS)
Omenn syndrome
DiGeorge syndrome (DGS)
Netherton syndrome, form of ichthyosis associated with SPINK5
Nezelof syndrome, congenital hypoplasia of the thymus with retention of normal parathyroid function (in contrast to complete DiGeorge syndrome in which there is absence of the parathyroids)

Defect of regulatory T cells in patients with Omenn syndrome. Cassani B, Poliani PL, Moratto D, Sobacchi C, Marrella V, Imperatori L, Vairo D, Plebani A, Giliani S, Vezzoni P, Facchetti F, Porta F, Notarangelo LD, Villa A, Badolato R. J Allergy Clin Immunol. 2010 Jan;125(1):209-216.
Mind Maps: Primary Immunodeficiency Disorders (PIDD)

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