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Congenital HLA class I deficiency is a rare disease frequently resulting in chronic inflammation of the respiratory tract, and/or skin granulomas.1,2 The deficiency may be unnoticed for decades, so pathological outcome is relatively unpredictable.3 We here describe a 14 year old patient with a severe ocular toxoplasmosis who is HLA class I deficient, as a result of a homozygous mutation in the gene encoding one of the two subunits of the peptide transporter associated with antigen processing (TAP). We propose that such a defect should be investigated in patients with severe ocular toxoplasmosis without acquired immunodeficiency.
At the time of referral, the patient did not have any particular medical history except an exaggerated reaction to an intradermal tuberculin test 1 year earlier. His right eye displayed a strong reduction of acuity with anterior and posterior inflammatory lesions and pain. There was corneal inflammation with flare in the anterior chamber, anterior uveitis with cellular deposits on the corneal endothelium (keratic precipitates) but without posterior synechiae and grade B3 vitritis. A focus of chorioretinitis was just visible in the macular area. The blood neutrophil count was high (14.49 white cells/×106/l with 13.48 neutrophils/×106/l), while serology showed high levels of anti-toxoplasma IgG (543 IU/ml) with an IgM index of 53.73. Anti-toxoplasma therapy was attempted by administration of sulfadiazine, pyrimethamine, and folinic acid for 2 days, followed by prednisone. Despite this treatment, the ocular inflammation worsened and led to loss of vision and ocular divergence. A clinical examination revealed posterior synechiae and aggravation of the vitritis and B echography showed retinal detachment (fig 1A).
Surgery was performed, which comprised pars plana vitrectomy after phacoemulsification, with ablation of the incompletely detached posterior hyaloid. The retina was reattached with silicone oil. The inferior retina appeared necrotic with a focus of inflammatory chorioretinitis in the macular area. Twelve months after surgery, the eye was no longer painful but vision was limited to perception of hand movements with ocular divergence (fig 1B). A fundus of the right eye revealed retraction of the inferior retina and extended gliosis of the macula (fig 1C).
The severity of the clinical manifestations prompted an evaluation of the patient’s immunocompetence, which appear to be normal, except that the amount of HLA class I molecules expressed on the plasma membrane of the lymphocytes was reduced 20-fold (figs 2 and 3). The parents were unrelated, but shared an identical HLA haplotype, so the patient and his brother were HLA homozygous (HLA-A*24; B*14; Cw*08; DRB1*13; DQB1*06). TAP genes, located in the HLA genetic region, were characterised, and a stop mutation in the TAP1 was identified at codon 522 (sequence AAS55412.1 in GenBank), because of a C to T substitution.
The patient did not display pulmonary involvement, contrary to his elder brother who displayed a bronchial obstruction unresponsive to inhaled bronchodilators, a bacterial colonisation of the lower airways associated to asthma-like symptoms, but no bronchiectasies.
The presence of anti-toxoplasma IgM suggests that the infection was recent and is compatible with a primary ocular infection. The particular titre of anti-toxoplasma IgG suggests that these antibodies might have had a role in the immunological defence, as has been observed for viral infections.4
Remarkably, during the pathology, more than 40% of the T cells of the patient were γδ, which can be explained by the infection, known to induce the expansion of this T cell subset.5,6 After recovery, this number decreased twofold.
These observations suggest that TAP deficiency should now be considered as a potential cause of unexplained exacerbated pathology in response to intracellular parasites, notably T gondii. In our patient, special follow up including prophylactic antibiotherapy is required, in order to avoid infection of the other eye.
We thank José Sahel and Claude Bénichou for critical reading of the manuscript. This work was supported by ARMESA, INSERM, and the Etablissement Français du Sang-Alsace.