The revolution in molecular biology leads to new understanding of the clinical expression of immunodeficiencies

Abstract

See related articles p 191 and p 194. In the past decade, dramatic advances in the fields of genetics and cellular and molecular biology have allowed us to identify not only the mutations that are responsible for many hereditary diseases, but also the physiologic consequences of these mutations. The well defined familial patterns of the hereditary periodic fevers have lent themselves particularly well to genetic analysis. As a result, genetic mutations specific to each of the 4 major hereditary periodic fever syndromes have been identified: mutations in the MEFV gene in familial Mediterranean fever,1A candidate gene for familial Mediterranean fever.Nat Genet. 2007; 17 (The French FMF Consortium): 25-31Google Scholar in the MVK gene in hyper IgD syndrome,2Drenth JP Cuisset L Grateau G Vasseur C van de Velde-Visser SD de Jong JG et al.Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome.Nat Genet. 1999; 22 (International Hyper-IgD Study Group [see comment]): 178-181Crossref PubMed Scopus (482) Google Scholar in the CIAS1 gene in familial cold urticaria and Muckle-Wells syndrome,3Hoffman HM Mueller JL Broide DH Wanderer AA Koldner RD Mutation of a new gene encoding putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome.Nat Genet. 2001; 29: 301-305Crossref PubMed Scopus (1298) Google Scholar and in the tumor necrosis factor (TNF) receptor superfamily gene TNFRSF1A in tumor necrosis factor receptor-associated periodic syndrome (TRAPS).4McDermott MF Aksentijevich I Galon J McDermott EM Ogunkolade BW Centola M et al.Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.Cell. 1999; 97: 133-144Abstract Full Text Full Text PDF PubMed Scopus (1109) Google Scholar Among the hereditary periodic fevers, a potential mechanism for the pathogenesis of disease is best delineated in TRAPS: mutations in the TNFRS1A gene appear to lead to decreased serum levels of soluble TNF receptor and consequent inflammation from TNF that is released but not cleared.5Galon J Aksentijevich I McDermott MF O'Shea JJ Kastner DL TNFRSF1A mutations and autoinflammatory syndromes.Curr Opin Immunol. 2000; 12: 479-486Crossref PubMed Scopus (233) Google Scholar Several mutations in the TNFRSF1A gene have been described to date in families or persons with TRAPS.6Drenth JPH van der Meer JWM Hereditary periodic fever.N Engl J Med. 2001; 345: 1748-1757Crossref PubMed Scopus (395) Google Scholar In the current issue, Weyhreter et al describe a new mutation in this gene in 4 family members with TRAPS.7Weyhreter H Schwartz M Kristenson TD Valerius H Paerregaard A A new mutation causing autosomal dominant periodic fever syndrome in a Danish family.J Pediatr. 2003; 142: 191-193Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Interestingly, mutations in a different tumor necrosis factor receptor superfamily gene, TNFSF5 , are responsible for the X-linked form of hyper immunoglobulin (Ig) M syndrome (HIGM) also termed HIGM1, which was first described in 1961.8Allen RC Armitage RJ Conley ME Rosenblatt H Jenkins NA Copeland NG et al.CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome.Science. 1993; 259: 990-993Crossref PubMed Scopus (766) Google Scholar, 9Rosen FS Kevy SV Merler E Janeway CA Gitlin G Recurrent bacterial infections and dysgammaglobulinemia: deficiency of 7S gammaglobulin in the presence of elevated 19S gammaglobulin.Pediatrics. 1961; 28: 182-195PubMed Google Scholar Children with HIGM1 have recurrent bacterial infections, as well as with infections usually associated with T-lymphocyte defects such as Pneumocysitis carinii , Cryptococcus neoformans , Cryptosporidium parvum , and Histoplasma capsulatum.10Hostoffer RW Berger M Clark HT Schreiber JR. Disseminated Histoplasma capsulatum in a patient with hyper IgM immunodeficiency.Pediatrics. 1994; 94: 234-236PubMed Google Scholar In HIGM1, mutations in TNFSF5 lead to defects in the expression of the CD4+ T-lymphocyte CD40 ligand (CD40L), which normally engages the B-lymphocyte CD40 receptor and is critical to efficient B-lymphocyte activation, and to upregulation of costimulatory signals to the T-lymphocyte. Impaired CD40 activation leads to limitations in B-lymphocyte proliferation, isotype switching to IgG, IgA, and IgE, and germinal center formation.11Foy TM Laman DJ Ledbetter JA Aruffo A Claassen E Noelle RJ gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory.J Exp Med. 1994; 180: 157-163Crossref PubMed Scopus (378) Google Scholar In the current issue, Kutukculer et al describe a girl with HIGM and disseminated Cryptosporidium parvum infection.12Kutukculer N Moratto D Aydinok Y Lougaris V Adsoylar S Plebani A et al.Disseminated Cryptosporidium infection in an infant with hyper IgM syndrome due to CD40 deficiency.J Pediatr. 2003; 142: 194-196Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Although her clinical presentation was classic for HIGM1, this X-linked syndrome was excluded because she was female. HIGM2, an autosomal recessive form of HIGM caused by mutations of the activation-induced cytidine deaminase gene was also unlikely because it typically manifests only with recurrent bacterial infections.13Revy P Muto T Levy Y Geissmann F Plebani A Sanal O et al.Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyper-IgM syndrome (HIGM2).Cell. 2000; 102: 565-575Abstract Full Text Full Text PDF PubMed Scopus (1340) Google Scholar The authors previously described 3 cases of autosomal recessive HIGM with recurrent pulmonary infections and Pneumocystis carinii pneumonia.14Ferrari S Giliani S Insalaco A Al-Ghonaium A Soresina AR Loubser M et al.Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM.Proc Natl Acad Sci U S A. 2001; 98: 12614-12619Crossref PubMed Scopus (307) Google Scholar In these patients, they documented mutations in the CD40 gene, which led to lack of surface expression of the CD40 receptor, and they termed this form of the syndrome HIGM3. The child in the current report was also found to have HIGM3 because of a novel mutation in the CD40 gene. Thus defects in 2 different cell lines (T and B lymphocytes), both of which involve CD40-CD40L interaction, can lead to a similar clinical syndrome of dysgammaglobulinemia and recurrent opportunistic infections. Interestingly, the infection reported is primarily one associated with defective T-lymphocyte function, not dysgammaglobulinemia, and previous studies show that similar “unexpected” opportunistic pathogens cause disease in HIGM1. Because CD40 is also found on dendritic cells, macrophages and thymic epithelial cells, defective CD40-CD40L interactions may lead to a disturbance in T-lymphocyte development and selection, causing a functional T-lymphocyte defect. Finding the cause of a clinical syndrome at the level of the gene is tremendously exciting for the scientist, but what does it mean to the clinician or the patient? Such testing is not, after all, routine in many tertiary care centers, and certainly not available in most community hospitals. Furthermore, both of the diseases described are rare: most pediatricians may never encounter either one. Studies like those by Weyhrehter et al7Weyhreter H Schwartz M Kristenson TD Valerius H Paerregaard A A new mutation causing autosomal dominant periodic fever syndrome in a Danish family.J Pediatr. 2003; 142: 191-193Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar and Kutukculer et al12Kutukculer N Moratto D Aydinok Y Lougaris V Adsoylar S Plebani A et al.Disseminated Cryptosporidium infection in an infant with hyper IgM syndrome due to CD40 deficiency.J Pediatr. 2003; 142: 194-196Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar are nonetheless relevant to clinicians and patients for several reasons. Recurrent fever in children is not uncommon. Awareness among the community of physicians of syndromes like the hereditary periodic fevers and their pathogenesis allows for recognition of those rare patients who have these diseases. Such patients should be referred to centers with specialists in infectious diseases, immunology, and genetics, where appropriate testing can be done. Similarly, knowledge of multiple forms of HIGM will allow clinicians to refer for more detailed testing those patients with HIGM who do not fit classic X-linked HIGM1 or to better define the cause of “combined” immunodeficiencies. Knowledge of the signs and symptoms of diseases like the hereditary periodic fevers also allows clinicians to avoid unnecessary testing in the vast majority of children with recurrent fevers, who, if otherwise healthy, require only minimal laboratory testing.15John CC Gilsdorf JR Recurrent fever in children.Pediatr Infect Dis J. 2002; 21: 1071-1077Crossref PubMed Scopus (42) Google Scholar Defining the precise disease defect at the gene level leads to an improved understanding of disease pathogenesis and consequently to new treatment options. In the case of TRAPS, knowledge of the defect in soluble TNF receptor and the inflammatory changes caused by unbound TNF led to the use of etanercept, a fusion protein that binds to TNF and attenuates its biologic activity. Early clinical trials of etanercept in a small number of patients with TRAPS have been promising,16Nigrovic PA Sundel RP Treatment of TRAPS with etanercept: use in pediatrics.Clin Exp Rheumatol. 2001; 19: 484-485PubMed Google Scholar and in the current report, an excellent clinical response was seen in the patient treated with etanercept. In the case of HIGM, the authors of the report in this issue point out that the bone marrow transplantation, which has been performed successfully in persons with HIGM1, might not have similar success in HIGM3, because transplantation would not correct the lack of expression of CD40 by endothelial and epithelial cells. In these diseases, knowledge of genetic mutations and cellular defects has already had a significant effect on therapeutic decisions. Mutations in a single gene that lead to a distinct disease are the simplest and most elegant demonstrations of genetic mutations at work. With the complete sequencing of the human genome, we can expect further studies to provide answers to some previously puzzling clinical entities. Such studies serve as starting points for the more involved analyses of common diseases, in which multiple genes may contribute to disease, and in which numerous other factors such as environment and diet may play a role. For persons considering or just beginning their pediatric training, the clinical reports in this issue demonstrate beautifully the practical clinical applications of basic science research and why it is such an exciting time to be either a physician scientist or clinician. Researchers have new and powerful tools to determine the precise mechanism of pathogenesis of “idiopathic” diseases, whereas the clinician will have innovative treatments based on this information with which to intervene in previously untreatable diseases. Disseminated cryptosporidium infection in an infant with hyper-IgM syndrome caused by CD40 deficiencyThe Journal of PediatricsVol. 142Issue 2PreviewWe report the case of an infant with severe respiratory infections, chronic diarrhea, failure to thrive, and disseminated Cryptosporidium parvum infection. Laboratory investigations disclosed a diagnosis of hyper-IgM syndrome caused by CD40 deficiency. Full-Text PDF