Immunity to Microbes: Lessons from Primary Immunodeficiencies

Abstract

Primary immunodeficiency diseases (PIDs) represent a large and heterogeneous group of more than 120 different entities, most of which have now been genetically characterized (77). Increased susceptibility to infections is the predominant manifestation of almost all forms of PID, particularly in infants and children, demonstrating the paramount importance of the immune system in defense against infection. It has long been known that the nature of an immune defect is related to the etiology of an infection. Prime examples are recurrent respiratory infections with pyogenic bacteria in patients with antibody deficiencies, opportunistic infections with fungi and viruses in infants with SCID (severe combined immunodeficiency), Neisseria meningitidis infections as a hallmark of defects in late-complement components, recurrent staphylococcal infections in patients with neutrophil disorders, and susceptibility to weakly virulent mycobacterial diseases and to Salmonella in patients with deficiencies of the interleukin-12 (IL-12)/IL-23-gamma interferon (IFN-γ) axis. Studies of PID patients have actually contributed to clarification of the anti-infection roles of several mechanisms and components of the immune response, as PIDs offer unique opportunities to link phenotypes to immunological functions and to ascribe various classes of immunity to defenses against different microbes. Thus, studies of agammaglobulinemic patients were crucial in elucidating the role of antibodies in immunity to extracellular bacteria and enteroviruses, as were studies of children with Kostmann's syndrome (congenital severe neutropenia) and chronic granulomatous disease (CGD) in defining the critical role of neutrophils and studies of SCID patients in showing the relevance of T-cell immunity in resistance to intracellular pathogens. More recently, as clinical phenotypes are being mapped to gene defects, respective pathophysiologies can be better understood, often with the help of murine knockout models. Here we offer an observational approach to host/parasite relationships, based on clinical features of PID patients. After an exhaustive review of the main infectious manifestations of PID patients described in large published series as well as in our own series, we propose a novel classification of PIDs according to the degrees of clinical susceptibility to infectious agents observed with PID patients, attempting to link selective susceptibility to specific mechanisms and to established genetic defects. Evidence for a causal association between a particular infection and a given PID is available in some cases, but in others, only a small number of patients have been studied. The data were organized in tables that classify susceptibility to each infection as high (when it is a major manifestation of disease), intermediate (when it appears in some cases but not as a rule), and low (when it is seldom seen). We believe that organizing available information in this manner may also be helpful for the physician, whose identification of a given infection may help determine a putative immunodeficiency.