DEFECTIVE EXPRESSION OF EARLY ACTIVATION GENES IN CARTILAGE-HAIR HYPOPLASIA (CHH) WITH SEVERE COMBINED IMMUNODEFICIENCY (SCID)

Cartilage-hair hypoplasia (CHH) is an autosomal recessive disease of u nknown etiology characterized by metaphyseal dysostosis, unpigmented h air, and defective cellular immunity. We studied peripheral blood mono nuclear cells (PBMC) of a boy with CHH and combined immunodeficiency i n an attempt to characterize further the immune defect in this disease . Stimulation of his PBMC with mitogens was associated with severely d epressed IL-2 and interferon-gamma (IFN-gamma) synthesis and IL-2 rece ptor alpha-chain (IL-2R alpha) expression and resulted in poor lymphoc yte proliferation that was only modestly upregulated by the addition o f recombinant IL-2 (rIL-2). The defective proliferation and lymphokine synthesis were not corrected by the addition of phorbol myristate ace tate (PMA) and ionomycin, agents that bypass receptor-mediated signall ing, indicative of a distal abnormality. Importantly, the levels of mR NA encoding c-myc, IL-2R alpha, IL-2 and IFN-gamma were markedly decre ased in patient lymphocytes stimulated with PMA + ionomycin as compare d to control lymphocytes The defect in the expression of these early a ctivation genes was selective in that induction by mitogens of mRNA en coding other early activation gene products such as c-fos and c-jun wa s not impaired. These results suggest that the underlying defect in th is patient and perhaps others with CHH may be an abnormality in a comp onent of intracellular signalling pathways or in a trans-acting factor which regulates the expression of a selected number of early activati on genes.