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Omenn syndrome is an autosomal recessive disease, and a form of severe combined immunodeficiency (SCID) that compromises the lymphatic system (Marella, Maina & Villa, 2011). The syndrome is often the result of mutations in the RAG1 and RAG2 genes on chromosome 11p13, ultimately affecting the variable (diversity) joining, V(D)J recombination pathway, which is critical for the immune response of T and B lymphocytes (Elnour et al., 2007). The syndrome is rare, affecting 1 in 50 000 children in the United States (Schwartz, 2012), with cellular mechanisms varying between clinical cases. Since Gilbert Omenn first described this syndrome in 1965, there have been seventy reported patients (Ege et al., 2005).
V(D)J recombination is comprised of a multi-step pathway that introduces a break in the variable, diversity or joining segments of DNA in the RAG-dependent phase, followed by its recombination with another segment and reattachment in the nonhomologous DNA end joining (NHEJ) phase (Leiber, 2003). This process generates a diverse set of exons that encode the variable regions of both immunoglobulin (Ig) and T-cell receptors (TCR) strictly during B and T cell maturation occurring in the bone marrow and thymus, respectively. The immense diversity of the variable regions of these lymphocytes and antibodies allows for the binding of numerous different types of antigens. B and T lymphocytes are vital when considering the effectiveness of the adaptive immune system.
The protein products of recombination-activating genes RAG1 and RAG2 initiate the RAG-dependent phase. The two enzymes form a complex to initiate recombination adjacent to V(D)J segments by introducing a nick in the strand, leaving a 3’ OH end which attacks the opposite strand to form a hairpin. The RAG complex binds to the recombination signal sequence (RSS), a gene segment composed of two consensus sequences, a heptamer CACACTG and a nonamer ACAAAAACC, separated by an unconserved 12- or 23-base pair spacer (Jones & Gellert, 2004). Upon recombination, different length spacer RSS’s most often recombine, 12bp to 23bp, according to the ‘12/23 rule’ (Hesse et al., 1989).
The NHEJ phase is initiated by a heterodimer protein Ku, which binds to the hairpin end, possibly displacing the RAG complex (Leiber, 2003) and recruits the DNA-protein kinase catalytic subunit (DNA-PKcs)/Artemis complex. This complex reopens the hairpin end and randomly trims the V, D or J segments, acting as an endonuclease to generate greatly increased levels of genetic variability. Finally, an X ray cross complementation 4 enzyme (XRCC4)/DNA-ligase IV complex rejoins the ends of the double strand (Figure 1).
Missense mutations in RAG1 or RAG2 can lead to Omenn syndrome by impairing the V(D)J recombination process (Figure 1). Omenn syndrome can be characteristically based on normal to higher than normal T cell counts and lower than normal or absence of B cells altogether, the latter being the more common in most patients. Though T cells are typically increased, they are non-functional, and eosinophil count is increased (Elnour et al., 2007). The elevated T cell counts are found most predominantly in the gut and skin, the phenotype being activated T cells, however, depletion of lymphocytes is observed in the thymus and lymphoid tissue, which is expected in patients with severe combined immunodeficiency (SCID): Omenn syndrome falls under this category (Elnour et al., 2007). The mutations that are present keep residual recombination activity which allows the T cell receptor gene to undergo some rearrangements occurring in the thymus. In most cases, the T cells are autologous, not maternal, and abnormal in many aspects – T cells become, for the most part, activated memory cells (Santagata et al., 2008). The response to mitogens is decreased and the Th2 type T cell receptor repertoire has oligoclonal expansions which causes it to be skewed. This skewing seems to be a factor in the facilitation of the key features of Omenn syndrome but, it is most likely not the primary factor that leads to it (Santagata et al., 2008).
Though the causes, development and all of the effects are not entirely understood or known at this point, it seems as though the characteristic features of Omenn syndrome are typically due to a deregulation of cytokine production by the activated T cells. Omenn syndrome includes an overrepresentation of Th2 type T cells, causing an increase in interleukin-4, interleukin-5, and interleukin-10 secretion as well as elevated IgE levels and eosinophilia (Santagata et al., 2008). IgE levels increase in the absence of B cells in peripheral blood, skin and lymph nodes. There are typically no circulating B cells despite the raised levels of IgE (Elnour et al., 2007). It is the increase in interleukin-5 that causes Th2 type T cell activation, which is what promotes eosinophil differentiation. The normal function of T cells is to promote IgE production however; they can also have an inhibitory effect on macrophages. It is generally accepted that the elevated IgE levels are directly linked to the dysfunction of the T cells (Elnour et al., 2007).
The rearrangements that are present are mediated by lymphoid specific proteins that are encoded by the recombination activating genes (RAG1 and RAG2). In most cases, B cells are missing and natural killer cells (NK) are present. Th2 type T cells are increased, leading to a huge increase in the release of inflammatory cytokines. The oligoclonal T cells are due to intrathymic restriction and to peripheral nerve expansion (Elnour et al., 2007). Mutations on the RAG1 and RAG2 gene have been associated with the phenotypic expression of Omenn syndrome (Calvo-Cavazzana & Villartay, 2005). These aforementioned mutations in RAG1 and RAG2 vary from T-cell negative (T-), B cell negative (B-), and natural killer cell positive (NK+) (Moshous et al., 2001). For all of these conditions, the mutations interfere with the active recombinase genes and typically limit the production of the recombinase protein, thus leading to a reduction of T-lineage and B-lineage cells. In Omenn syndrome, RAG1 and RAG2 proteins are normally distributed in the nucleus of cells. Missense mutations on chromosome band 11p13 of RAG1 and RAG2 have been implicated in many cases of Omenn syndrome, and R396C on the RAG1 gene is considered to be a true example of the syndrome (Elnour et al., 2007).
Human cases of SCID are characterized by a defect in this V(D)J recombination. Mutations in RAG1 or RAG2 abrogate the V(D)J recombination process and result in noticeably reduced T and B cell counts, due to inhibited lymphocytic maturation (Moshous et al., 2001). RAG mutations, however, are not limited to missense mutations; frameshift mutations within the 5’ coding region of RAG1 have also been implicated in phenotypes synonymous with Omenn syndrome (Santagata et al., 2000). Additionally, the N terminus of RAG1 has been recognized as having the capacity to enhance the efficiency of the V(D)J recombination reaction. Omenn syndrome that is a result of one or two nucleotide deletions at the N terminus of RAG1 leads to the production of nonfunctional RAG1 fragments that lack portions of the C terminus (Santagata et al., 2000). However, RAG mutations are not compulsory for the expression of the disease: reduced V(D)J recombinase activity may not always be sufficient to cause the Omenn syndrome phenotype. Based on the plethora of cellular mechanisms, all of which vary in complexity, Omenn syndrome has several derivatives. Further studies are needed to examine the genetic components related to this syndrome, with a particular focus on RAG1 and RAG2 and their relationship with V(D)J recombination.
Gilbert Omenn published a study which described for the first time the symptoms, attempted treatments, and pedigree of an infant boy with a disease of the reticuloendothelial system and eosinophilia (Omenn, 1965). The boy in question was one of 12 infants affected by the disease, all of whom came from six sibships, and succumbed to the disease (Omenn, 1965). The evidence he provided supported the hypothesis that the disease in question was due to the inheritance of an autosomal recessive gene. The pedigree he studied was that of a large, highly inbred Irish Catholic family, and the results of this study helped distinguish the disease from Letterer-Siwe disease, of which the effects had only ever been recorded within one sibship (Omenn, 1965). Villa et al., (1998) analyzed seven Omenn syndrome patients, all of whom had recessive/missense mutations in either RAG1 or RAG2 genes. The mutations disrupted RAG1 and RAG2’s ability to participate in the rearrangement of antigen receptor loci (V(D)J recombination), and ultimately led to the presence of immature B and T lymphocytes and immunodeficiency (Villa et al., 1998). Their results suggest that mutations in the RAG1 and RAG2 genes can: a) affect RAG1’s ability to bind to DNA, b) affect the formation of the RAG1/RAG2 complex and c) affect the cleavage abilities of the RAG1/RAG2 complex (Villa et al., 1998). Two of the amino acid (AA) substitutions they observed occurred within the RAG1 gene and decreased its DNA binding activity, while three other AA substitutions negatively affected the interaction between RAG1 and RAG2 (Villa et al., 1998).
Corneo et al. (2001) reported nine cases of Omenn syndrome and analyzed the mutations in RAG1 and RAG2 genes, three of which have also been seen in patients with T-cell-B-cell-SCID (T-B-SCID). Results suggested that a mutation in the RAG1 or RAG2 genes may not be the only thing causing Omenn syndrome. Eleven mutations in RAG1 and RAG2 were identified, and the patients were either homozygotes or compound heterozygotes, and the mutations had always been inherited from the parents (Corneo et al., 2001).
Nonsense mutations or deletion of one or more nucleotides, leading to premature stop codons, was seen in three patients, which usually results in T-B-SCID, however the patients presented with partial, or 'leaky', V(D)J recombination (Corneo et al., 2001). It was assumed that another initiation site existed further downstream from the mutation, leading to partial transcription (Corneo et al., 2001). The RAG2-R229Q mutation, RAG1-R561H mutation, and RAG1 ΔT631 mutation have been detected in Omenn syndrome patients and T-B-SCID patients (Corneo et al., 2001). After sequencing the ARTEMIS gene, Ege et al. found a compound heterozygosity in the NHEJ factor. Humans that lack this ARTEMIS protein due to mutations present with T-B-SCID, and B cell development is absent (Ege et al., 2005). There have been Omenn syndrome patients that did not have mutations in RAG1 or RAG2, and it was hypothesized that they had mutations in ARTEMIS or other molecules involved in the V(D)J recombination process (Ege et al., 2005) This paper presented a case of Omenn syndrome with no RAG mutations, and reported that the presence of ARTEMIS mutations was the cause of the Omenn syndrome (Ege et al., 2005).
The “classical” form of Omenn syndrome is due to hypomorphic mutations, which cause a partial loss of gene function in the RAG genes involved in V(D)J recombination (Marella et al., 2011). “Omenn-like” features present when there are mutations in the genes responsible for the maturation of lymphoid cells, not in genes involved in V(D)J recombination (Marella et al., 2011). At the time of this review, four genes participating in V(D)J recombination were known to show mutations in Omenn syndrome patients, but the mutations did not cause complete loss of gene function, therefore T cells were still produced (Marella et al., 2011). There have been cases of Omenn syndrome without mutations in the RAG genes, for example, the M1T mutation in the the gene encoding ARTEMIS, and this indicates that mutations in other genes involved in the V(D)J recombination or NHEJ pathway can lead to Omenn syndrome (Marella et al., 2011).
In short, Omenn syndrome initially, and most frequently, is associated with mutations in RAG1 or RAG2. However, as research has developed, more mutations have been discovered that result in the expression of an Omenn syndrome phenotype. Many mutations lead to Omenn-like syndrome and SCID, which may differentiate only slightly from the ‘classic’ Omenn syndrome.
The symptoms include:
Allogeneic bone marrow transplant: Bone marrow transplants are usually the choice of therapy for treatment of Omenn syndrome. It is important to match the donor and the recipient of the bone marrow transplant; therefore, a major histocompatibility complex (MHC) typing is done. Omenn syndrome in human patients can be cured with human leukocyte antigen (HLA)-identical or haploidentical bone marrow transplants, given that they are fed parenterally in order to improve nutritional status, and that they are given immunosuppressive therapy before transplantation (Gomez et al., 1994). Although a related HLA-identical donor (RID) from a family member is ideal, HLA-mismatched related donors (MMRDs) or HLA-matched unrelated donors (MUDs) can be used if there are no RIDs. Compared to RIDs, which have about 92.3% survival rate, MUDs and MMRDs are associated with a significantly lower survival rate, although MUDs have a higher survival rate than MMRDs (Grunebaum et al., 2006).
