****This web page was produced as an assignment for an undergraduate course at Davidson College.****
Omenn's Syndrome
An Interesting Immune-related Disease
An Introduction to Omenn’s Syndrome
Omenn’s syndrome is an autosomal recessive early-onset form of severe combined immunodeficiency (SCID) characterized by increased susceptibility to opportunistic infections, hypereosinophilia, protracted diarrhea, rashes, and the enlargement of the lymph nodes and the spleen. Its presentation is very similar to that of graft-versus host disease (GVHD) insofar as T cells in individuals with Omenn's syndrome recognize and attack self cells (Janeway et al., 2005).
If not treated properly, Omenn's syndrome will prove fatal within the first two to six months of life (Omenn, 1965).
Omenn's syndrome is also known as combined immunodeficiency with hypereosinophilia (Rieux-Laucat et al., 1998).
Omenn's syndrome was first characterized in 1965 by Gilbert S. Omenn while he was a fourth-year student at Harvard Medical School. He described the condition as reticuloendotheliosis with eosinophilia (Omenn, 1965).
The Immune System in Patients with Omenn's Syndrome
Individuals with Omenn’s syndrome exhibit a normal or a high level of circulating T cells in the blood and in the tissues of the skin, the intestine, the spleen, and the liver. The thymus, however, is almost completely devoid of T cells (Giliani et al., 2006). T cells in individuals with Omenn's syndrome exhibit an abnormal and very narrow T-cell antigen receptor (TCR) repertoire in the peripheral lymphoid organs; the CDR3 variable region of the TCR β chain in both CD4 and CD8 T cells shows only a very limited diversity. The presence of abundant quantities of T cells in specific tissues indicates that the limited TCR repertoire may target antigens present in these tissues. This explains both the rashes and the diarrhea associated with Omenn's syndrome (Rieux-Laucat et al., 1998).
T cells in individuals with Omenn's syndrome respond poorly to antigens and to allogeneic cells, explaining the susceptibility to opportunistic infections (Giliani et al., 2006). Elevated serum levels of IL-4, IL-5, and IL-10 indicate the Omenn's syndrome leads to an overexpression of Th2 cells (Villa et al., 1998).
Individuals with Omenn's syndrome usually lack circulating B cells, resulting in severe hypogammaglobulinemia, or decreased levels of circulating IgG in the serum. Unexpectedly, elevated serum levels of IgE accompany the hypogammaglobulinemia (Rieux-Laucat et al., 1998).
Another Marker for Omenn's Syndrome
B and T cells in individuals with Omenn's syndrome completely lack ecto-5'-nucleotidase activity. Ecto-5'-nucleotidase is an enzyme that functions in purine metabolism and plays a role in normal lymphocyte development. Its absence from T and B cells in individuals with Omenn's syndrome distinguishes this disease from GVHD, in which ecto-5'-nucleotidase activity may be decreased but not absent (Gelfand et al., 1984).
The Causes of Omenn's Syndrome
Omenn’s syndrome may arise from any one of multiple genetic mutations.
Some individuals with Omenn’s syndrome possess missense mutations in the genes encoding the lymphoid-specific enzymes RAG-1 and RAG-2, which play a central role in the V(D)J recombination activities that result in TCR diversity. These mutations restrict the enzymes’ activities but do not entirely eliminate their functions. Four of these mutations, Rag-1 R561H, Rag-1 D429G, Rag-2 C41W, and Rag-2 M285R disrupt the interactions between the two enzymes when they form RAG-1/RAG-2 recombinase prior to beginning their role in V(D)J recombination. Another missense mutation, Rag-1 R396, reduces the capability of RAG-1 to bind to the recombination signal sequences (RSSs) that flank the gene segments involved in V(D)J recombination. The resulting low-affinity binding of RAG-1 to RSSs might drive V(D)J recombination in a specific direction, explaining the narrow TCR repertoire in individuals with Omenn's syndrome (Villa et al., 1998).
Other Rag-1 mutations are characterized by the deletion of one or two nucleotides from the N-terminus encoding end of the gene for RAG-1, resulting in a frameshift mutation that leads to the early termination of the enzyme at the C terminus. It appears as though the mutated Rag-1 gene is transcribed starting at the first methionine-encoding sequence downstream from the frameshift mutation. This maintains the proper reading frame at the C terminus of the protein. The resulting truncated protein is capable of performing limited V(D)J recombination. It appears that, although RAG-1 will function with a mutant N terminus, efficient recombinase functioning requires an intact RAG-1 N terminus. (Santagata et al., 2000).
Mutations in the gene encoding Artemis, an enzyme involved in opening the covalently closed DNA hairpin that forms during V(D)J recombination, also lead to Omenn's syndrome. The mutant phenotype leads to a decrease in the number of recombination events occurring within an individual's T cells. The mutation appears to be located in the gene's translation initiation codon and results in a 25% V(D)J recombination efficiency rate (Ege et al., 2005).
A missense mutation in the IL7RA gene, which encodes for the α chain of the interleukin-7 receptor, also appears to lead to Omenn's syndrome. This mutation affects T-cell development without affecting B-cell development, accounting for a subset of individuals with Omenn's syndrome who possess circulating B cells (Giliani et al., 2006).
Treatments
There is no known cure for Omenn's syndrome.
Unless treated with a bone marrow (haematopoetic stem cell) transplantation, Omenn's syndrome is fatal within the first few months of life.
In a successful bone marrow transplant, the individual is irradiated to kill all T cells with the Omenn's syndrome phenotype before healthy bone marrow is transplanted into the recipient. A regimen of immunosuppressant drugs prevents graft regection, and antibiotics protect the recipient from common diseases.
Because individuals with Omenn's syndrome are severely immunocompromised, there is a high transplantation mortality rate. Controlling T-cell activation and proliferation with immunosuppressive drugs, administering antibiotics, applying topical steroid creams to control the rash, and providing proper nutrition to compensate for diarrhea before the transplant increases the likelihood of success. Pre-transplantation treatment with cyclosporin A, an immunosuppressive drug, leads both to an improved disease phenotype and to a greater likelihood of a successful transplant (Meyer-Bahlburg, 2002).
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Literature Cited
Ege, M., Ma, Y., Manfras, B., Kalwak, K., Lu, H., Lieber, M. R., Schwarz, K., Pannicke, U. 2005. Omenn syndrome due to ARTEMIS mutations. Blood. 105(11): 4179-4186.
Gelfand, E. W., McCurdy, D., Rao, C. P., Cohen, A. 1984. Absence of lymphocyte ecto-5'-nucleotidase in infants with reticuloendotheliosis and eosinophilia (Omenn's syndrome). Blood. 63(6): 1475-1480.
Giliani, S., Bonfim, C., de Saint Basile, G., Lanzi, G., Brousse, N., Koliski, A., Malvezzi, M., Fischer, A., Notarangelo, L. D., and Le Deist, F. 2006. Omenn syndrome in an infant with IL7RA gene mutation. J. of Pediatrics. 148(2): 272-274.
Janeway, C. A., Travers, P., Walport, M., Sclomchik, M. J. 2005. Immunobiology: the immune system in health and disease, 6th ed. Garland Science Publishing, NY, pp. 753-777.
Meyer-Bahlburg, A., Haas, J. P., Haase, R., Eschrich, U., Wawer, A., Frank, L., Marsch, W. C., Burdach, S., Horneff, G. 2002. Treatment with cyclosporin A in a patient with Omenn's syndrome. Arch. Dis. Child. 87: 231-233.
Omenn, G.S. Familial reticuloendotheliosis with eosinophilia. 1965. New Eng. J. Med. 273(8): 427-432.
Rieux-Laucat, F., Bahadoran, P., Brousse, N., Selz, F., Fischer, A., Le Deist, F., De Villartay, J.P. 1998. Highly restricted human T cell repertoire in peripheral blood and tissue-infiltrating lymphocytes in Omenn's syndrome. J. Clin. Inves. 102(2): 312-321.
Santagata, S., Gomez, C. A., Sobacchi, C., Bozzi, F., Abinun, M., Pasic, S., Cortes, P., Vezzoni, P., Villa, A. 2000. N-terminal RAG1 frameshift mutations in Omenn's syndrome: internal methionine usage leads to partial V(D)J recombination activity and reaveals a fundamental role in vivo for the N-terminal domains. Proceedings of the National Academy of Scence USA. 97(26): 14572-14577.
Villa, A., Santagata, S., Bozzi, F., Giliani, S., Frattini, A., Imberti, L., Gatta, L.B., Ochs, H. D., Schwarz, K., Notarangelo, L. D., Vezzoni, P., Spanopoulou, E. 1998. Partial V(D)J recombination activity leads to Omenn syndrome. Cell. 93(5): 885-896.
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Contact me. (Summerlee Walter) suwalter@davidson.edu