Human monogenic disorders that confer predisposition to specific infections

Capucine Picard*f, Laurent Abel* and Jean-Laurent Casanova*^

* Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes-INSERM U550, Faculté de Médecine Necker, 156 Rue de Vaugirard, 75015 Paris, France, f Centre d'étude des déficits immunitaires, Hôpital Necker-Enfants Malades, 149 Rue de Sèvres, 75015 Paris, France and f Unité d'Immunologie et d'Hématologie Pédiatriques, Hôpital Necker-Enfants Malades, 149 Rue de Sèvres, 75015 Paris, France

Abstract. Human monogenic disorders affecting immunity to infection are increasingly recognized. Most are associated with primary immunodeficiencies, which typically confer predisposition to multiple infectious diseases. We review here the known, atypical monogenic disorders that confer a narrow vulnerability to infection with specific microorganisms in otherwise healthy individuals. These 'experiments of nature' have important immunological and clinical implications.

2007 Decoding the genomic control of immune reactions. Wiley, Chichester (Novartis Foundation Symposium 281) p 65—78

Only a minority of infected individuals develop clinical disease and human genes play an important role in determining susceptibility or resistance (Casanova & Abel 2005). Predisposition or resistance to infectious disease may follow a simple or complex pattern of inheritance. Inborn errors of immunity affecting a single gene (described as Mendelian) are often referred to as primary immunodeficiencies (PIDs). PIDs include over 200 known clinical syndromes, at least 100 of which have a well defined molecular genetic basis (Notarangelo et al 2004). PIDs are typically associated with multiple and recurrent infections caused by weakly virulent (opportunist) microorganisms. However, severe opportunistic infectious diseases, often recurrent, have also been described in otherwise healthy individuals. The high frequency of familial forms, parental consanguinity, or both, suggested that these 'idiopathic' infections reflected a Mendelian predisposition. This intriguing group of 'non-conventional' PIDs (Casanova et al 2005), characterized by a narrow spectrum of specific infections, limited to one microbial genus or species, is small but expanding (Casanova et al 2002, 2005, Casanova & Abel 2004b, 2005). The specificity of predisposition to infections is not absolute, but these disorders are readily distinguished from other, 'conventional' PIDs on purely clinical grounds. The discovery of similar phenotypes and their corresponding genotypes in mice, with natural mutations conferring vulnerability to specific infections (e.g. Mx, Bcg, Lps, Cmv), has opened up new, fundamental avenues of research in molecular immunology (Casanova et al 2002). We review here the well documented monogenic disorders known to confer susceptibility to specific infections in humans, focusing on immunological implications.

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