A novel intronic splice site deletion of the IL-2 receptor common gamma chain results in expression of a dysfunctional protein and T-cell-positive X-linked Severe combined immunodeficiency.

X-linked severe combined immunodeficiency is caused by mutations in the IL-2 receptor common gamma chain and classically presents in the first 6 months of life with predisposition to bacterial, viral and fungal infections. In most instances, affected individuals are lymphopenic with near complete absence of T cells and NK cells. We report a boy who presented at 12 months of age with Pneumocystis jiroveci pneumonia and a family history consistent with X-linked recessive inheritance. He had a normal lymphocyte count including the presence of T cells and a broad T-cell-receptor diversity, as well as normal surface expression of the common gamma chain (CD132) protein. He however had profound hypogammaglobulinaemia, and IL-2-induced STAT5 phosphorylation was absent. Sequencing of IL-2RG demonstrated a 12-base pair intronic deletion close to the canonical splice site of exon 5, which resulted in a variety of truncated IL2RG mRNA species. A review of the literature identified 4 other patients with T-cell-positive X-SCID, with the current patient being the first associated with an mRNA splicing defect. This case raises the question of how a dysfunctional protein incapable of mediating STAT5 phosphorylation might nonetheless support T-cell development. Possible explanations are that STAT5-mediated signal transduction may be less relevant to IL7-receptor-mediated T-cell development than are other IL7R-induced intracellular transduction pathways or that a low level of STAT5 phosphorylation, undetectable in the laboratory, may be sufficient to support some T-cell development.

Is Roifman syndrome an X-linked ciliopathy with humoral immunodeficiency? Evidence from 2 new cases.

Roifman syndrome is a rare syndrome of bone dysplasia, growth retardation, retinal dystrophy and humeral immunodeficiency. Six cases have been reported to date, all of whom are male. We report a boy with clinical features of Roifman syndrome, whose older sister has skewed X-inactivation and a milder phenotype of the same disorder, supporting the hypothesis that this is an X-linked recessive condition. Both children had previously had a provisional diagnosis of Jeune dysplasia, and the boy had neonatal hip X-rays which demonstrated 'acetabular spurs' which are seen in a number of diseases thought to be caused by dysfunction of nonmotile cilia, including Jeune asphyxiating thoracic dystrophy. This finding in combination with other features such as retinal dystrophy, hepatic and renal disease suggests that the gene which is affected in Roifman syndrome may be involved with the function of nonmotile cilia and that Roifman syndrome may be the first example of a ciliopathy with associated immunodeficiency.

A 5th type of hypersensitivity reaction: does incidental recruitment of autoreactive effector memory T-cells in response to minute amounts of PAMPs or DAMPs, underlie inflammatory episodes in the seronegative arthropathies and acute anterior uveitis?

There are many documented associations of the HLA B27-related diseases--the seronegative arthropathies (SNAs) and acute anterior uveitis (AAU). However, to date no single pathogenic mechanism has been proposed which can account for more than a few of these associations. The hypothesis presented in this paper is that individual inflammatory episodes in the SNAs and HLA B27 AAU are initiated locally within the inflamed site, in response to tiny quantities of innately recognised molecules--pathogen associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs). However, clinically significant responses to such small amounts of PAMPs/DAMPs only occur in those individuals who possess pre-existing tissue-specific autoreactive effector memory T-cells, which once recruited into the tissue where their autoantigen resides, can mediate inflammatory damage. The mechanism put forward here could explain much of the research evidence and distinguishing clinical features of the HLA B27-associated diseases. These include: the well documented involvement of micro-organisms and tissue damage in these diseases; the more frequent involvement of certain organs compared with others; the often local and asymmetrical presentation of the SNAs/AAU, which contrasts with other autoimmune diseases that effect many sites in a more diffuse/symmetrical pattern; the fact that these diseases which are thought to be mediated by T-cells, are nonetheless refractory to treatment with T-cell activation blockers. Finally, if correct, the mechanism would define a 5th type of clinical hypersensitivity reaction, one manifested by an excessive reaction to small pro-inflammatory signals, in individuals who possess tissue-specific autoreactive effector memory T-cells.