Primary immunodeficiency diseases: an update

Abstract

The last full report of the IUIS Scientific Committee for Primary Immunodeficiencies [PIDs] was published in Clinical and Experimental Immunology over 3 years ago [1]. This covered the relevant basic immunological principles, cellular, genetic, humoral (including cytokine) and induction aspects of immune responses to those microbial antigens involved in human infections. All primary immunodeficiencies (and the investigations required for diagnosis) are discussed in turn, ranging from combined deficiencies of T and B cells, predominantly humoral defects, T cell defects (including those of cytokine and cytokine receptor production), complement and phagocyte deficiencies and those immunodeficiencies associated with genetic defects in related systems. A section on therapies and brief descriptions of causes of secondary immunodeficiencies completed the knowledge of ID known at that time. The report was timely and has been much quoted in the literature as a reference point for papers on mechanisms of both PID diseases and their treatments. The citation index must be substantial. The most recent meeting of this committee took place in July 2001. During the intervening 2 years there were few new types of PID; most of the newly described diseases were extensions of current phenotypes such as: recently described enzymes in established pathways (e.g. in VDJ recombination (Artemis), STAT1 in interferon:IL-12 pathways); another immunoglobulin isotype switch defect enzyme (AID) presenting as autosomal hyper IgM; a new DNA repair enzyme resulting in another ataxia-like syndrome; an interaction where previously only one of a pair of ligands had been identified as missing (e.g. CD40). Thus a major review was not necessary. The logical progression through the various ways in which parts of the immune system fail make these tables a useful starting point for newcomers to this field. This has also enabled new diseases and those illustrating some newer concepts to be fitted in easily to the existing format. There are some new concepts, such as: selective loss of CD8+ cells (CD8 deficiency), which may/may not turn out to be a lineage differentiation problem; finding a human corollary of a known mouse defect (Winged Helix Nude); another X-linked disease, explaining one form of ectodermal dysplasia; perhaps there may be more? two new forms of leucocyte adhesion defect, with new receptor/pathways to be explored. There are insufficient advances to reconfigure the tables or to subdivide in a more meaningful way at this stage. The revised tables below (Tables 1–3 and ​and5)5) should be read in conjunction with the text published previously. This update provides an excellent opportunity to re-emphasize that many developments in basic immunology have been suggested by/discovered alongside newly described PIDs. This is due to extensive investigation of patients in whom a diagnosis of one of the current 90 or so PIDs is not possible. Such patients provide a rich resource for identifying new genes that turn out to be important in normal immune responses. Hence new pathways are discovered and this results in the wider interest of basic immunologists, completing a longstanding and fruitful collaboration between clinical and basic science. Scientists are hugely important in studying those patients recognized by physicians to have an immune defect (due to the nature and frequency of infections), but in whom there is no clear diagnosis. This is especially relevant in those patients with a family history of the same disease phenotype or from consanguineous marriages, in whom autosomal recessive diseases are most common. Table 1 Combined immunodeficiencies Table 3 Other well-defined immunodeficiency syndromes Table 5 Congenital defects of phagocytic number and/or function It is encouraging to note the increasing prevalence of many PIDs. This may be due partly to improved techniques for diagnosis, but the collaborative development of definitions and simple ‘diagnostic criteria’ for use worldwide has undoubtedly played a role [2]. The production of a new major text devoted to PIDs (now in a second edition) has emphasized that the study of PIDs has come of age. The role of these diseases in the successful application of gene therapy helps to underline this. The next meeting of the IUIS Scientific Committee for Primary Immunodeficiencies is to be held in June 2003. There will be a detailed review of known PIDs at that time and we can look forward to more excitement in the form of new diseases and increased knowledge of immune pathways relevant to protection against infection in humans. Each advance is accompanied by improved diagnostic tests and new technologies result in improvements in therapy. There has never been a better time to enter this exciting and rapidly moving field of immunobiology.