CHAPTERIII Erkrankungen 22 der Genitalorgane Primary Immunodeficiencies structural genes, and also perhaps on the lack of 2/4 C4 A World in Motion genes [506]. MBL deficiency is due to one of three point mutations in the gene for MBL, each of which reduces Primary immunodeficiencies (PIDs), once considered levels of the lectin by interfering with the protein to be very rare,are now increasingly recognized because oligomerization [351]. In children with this kind of of growing knowledge in the immunological field and deficiency, the level of MBL is 4.9 mg/l compared to the the availability of more sophisticated diagnostic tech- 143 mg/l in controls [487]. Regardless of whether the niques and therapeutic modalities [161]. However in a children are homozygote (HZ) or heterozygote (HET) in database of >120,000 inpatients of a general hospital for relation to a given mutation, the defect appears to be conditions suggestive of ID 59 patients were tested, and more consistent in small babies aged 6–18 months [487], an undiagnosed PID was found in 17 (29%) of the sub- who show an immaturity in providing immune re- jects tested [107]. The publication of the first case of sponse to capsular bacteria and in whom low levels of agammaglobulinemia by Bruton in 1952 [60] demon- opsonin are incapable of compensating for this [506]. strated that the PID diagnosis is first done in the labora- The risk of contracting infections is similar in HZs [175] tory. However, PIDs require specialized immunological and HETs [486], though it persists throughout life in centers for diagnosis and management [33]. A large HZs because of an abnormal allele, while it exhausts it- body of epidemiological evidence supports the hypoth- self in the HETs, where the frequency of abnormality is esis of the existence of a close etiopathogenetic relation similar to that of the general population [175]. Anom- between PID and atopy [73]. In particular, an elevated alies in immunoglobulins (Ig) and in opsonization have frequency of asthma, food allergy (FA), atopic dermati- been observed, respectively in 13%–20% of children tis and enteric pathologies can be found in various PIDs. suffering from frequent asthma and IgG subclass defi- In addition we will discuss another subject that is cer- ciencies. Children suffering from cystic fibrosis also pre- tainly of interest: the pseudo-immunodepressed child sent an elevated prevalence of immediate cutaneous re- with recurrent respiratory infections (RRIs), an event actions to aeroallergens, and although without primary that often requires medical intervention and that very defects of adoptive immunity, they are susceptible to se- often leads to the suspicion that it involves antibody vere RRIs; therefore it may be possible that they suffer deficiencies [149]. from the mucosal antigenic exclusion [61]. Unlike asth- matic children, in whom a relatively high concentration of IgE for respiratory viruses was observed [172, 173, Immunodeficiency and Atopy 457], positive skin prick tests (SPTs) are more common for Aspergillus fumigatus [61]. In several PIDs (Table 22.1) [61, 65, 76, 101, 162, 351, 414, The hypothesis suggested by these observations is that 480, 514, 543], atopic symptoms are present: gastroen- atopy derives from an unbalanced immune response to teric and rhinitis in selective IgA deficiency (SIgAD), foreign antigens, with a consequent lack of their early severe AD in Wiskott-Aldrich syndrome (WAS) and identification or the capacity to neutralize or eliminate hyper-IgE syndrome (HIgES), in which it spreads over them. This hypothesis is based on the evidence that ID the entire body, and to which other allergic manifesta- precedes the development of atopy: in the Taylor et al tions can also be associated such as asthma, rhinitis and studies, 22 newborn babies, the children and/or siblings angioedema. Various acquisitions indicate that PID is of atopic patients, presented a significant reduction in also an opsonization deficiency, observed in 5% of the serum concentrations of IgA when aged 3 months: this normal population [469]. In this disease, microorgan- was transient hypogammaglobulinemia (hgG) of infancy ism phagocytosis by polymorphonuclear (PMN) leuko- (THI). The association of very low IgA levels with atopy cytes appears annulled, and the patient is subject to has been proposed again in the classic prospective study severe infections supported by capsular bacteria: the on the association of viral respiratory infections (VRI) deficiency, described in association with severe and and the onset of allergic manifestations, which proved recurrent infantile infections [175, 485, 487], depends serum IgA levels at the lowest normal levels in the chil- on the lack of mannose-binding lectin (MBL) [487], its dren studied [173]. This data has been confirmed within 1266 CHAPTER 22 Primary Immunodeficiencies Table 22.1. Primary immunodeficiency diseases Classification and inheritance Chromosome Gene defect A. Predominantly B-cell deficiency 1. Agammaglobulinemia or Bruton’s tyrosine kinase deficiency, XL Xq21.3–22 Btk a. Pre-BcR b. AR c. Surrogate light chain 22q11.22 d. m heavy (H) chain 14q32 2. Gene deletion for H chains, AR 14q32.3 3. k-chain deficiency, AR 2p12 IGKG 4. Selective Ig deficiency a. IgG subclass deficiency with or without IgA deficiency 14qx32.33 IGHG b. Selective IgA deficiency, AR 6p21.3 IGAD 5. Selective antibody deficiency with normal Ig isotypes (SADNI) 6. Selective deficiency of other Ig 7. Common variable ID, AR, AD associated with antibody deficiency (IgA) 6p21.3 8. Transient hypogammaglobulinemia of infancy (THI) B. Combined T-cell and B-cell deficiency 1. T–B+ SCID a. X-linked (SCID-X1) Xq13–21.1 IL2Rg gc Gene mutations Xq13.1 gc Gene mutations with an atypical NK phenotype b. Autosomal recessive JAK3 gene mutations 19p13.1 JAK3 IL7Ra deficiency 5p13 IL7Ra mutation CD45 deficiency 1q31-32 2. T–B– SCID a. RAG1 or RAG2 deficiency 11p13 RAG1 or RAG2 b. ADA (adenosine-deaminase) deficiency, AR 20q13.11 ADA c. Reticular dysgenesis, AR d. Radiation sensitive, AR 10p13 Artemis 3. T+B– SCID Omenn syndrome, AR IL2Ra deficiency, AR (IL2Ra-chain gene mutations) 11p13 IL2Ra 4. Hyper-IgM or CD154 deficiency, XL, AR Xq26.3–q27.1 CD154 Non-X-linked hyper-IgM (or hyper-IgD) syndrome 5. Purine-nucleoside-phosphorylase (PNP), AR 14q13.1 PNP 6. HLA (major histocompatibility complex) a. HLA class II antigen deficiency, AR 16p13.3 CIITA b. HLA class II antigen deficiency 1q21 RFX5 Deficit in RFXAP 13q14 RFXAP Deficit in RFXANK 19p12 RFXANK c. HLA class I antigen deficiency 13q Classification and Inheritance 1267 Table 22.1. (Continued) Classification and inheritance Chromosome Gene defect 7. CD3g, or CD3e, or CD3 deficiency, AR 11q23 CD3g/e 8. CD3d 9. ZAP-70 or CD8 deficiency, AR 2q12 ZAP-70 10. TAP-2 deficiency 6p21.3 11. NFAT deficiency, AR 12. NK-cells deficiency 13. Undifferentiated SCID Human nude SCID p56lck SCID, AR whn C. Predominantly T-cell defects 1. Primary CD4 T cell deficiency 2. Primary CD7 T cell deficiency 3. Multiple cytokine deficiency NFAT 4. Nezelof syndrome 5. Fas (CD95) deficiency D. Other well-defined immunodeficiency syndromes 1. Wiskott-Aldrich syndrome, XL Xp11.22–11.3 WASp 2. Ataxia telangiectasia, AR 11q22.23 ATM a. Nijmegen breakage syndrome, AR 8q21 NBS 3. DiGeorge syndrome 22q11.2 DGCR a. DiGeorge and Del 22q11.2 syndromes 10p13 4. X-linked lymphoproliferative syndrome, XLP Xq24–26 SH2DIA gene 5. Hyper-IgE syndrome 4q 6. Chédiak-Higashi syndrome 1q41.1–1q42.2 LYST 7. Cartilage hair hyperplasia, AR 9p13 RMRI mutation E. Phagocyte deficiency 1. Chronic granulomatous disease, XL a. X-linked (deficiency of 91-kD binding chain of cytochrome b) Xp21.1 gp91phox b. Autosomal recessive (deficiency of cytosol factors) p22phox 16q24 CIBA p47phox 7q11.23 NCF1 p67phox 1q25 NCF2 2. Leukocyte adhesion deficiency (LAD) a. LAD type I, AR 21q22.3 CD18 b. LAD type II, AR 11 CD15s c. LAD type III CD63E d. LAD type IV, AD e. LAD type V, AR 22q12.3 Rac 3. Deficiency of multiple leukocyte integrins 4. Glucose-6-phosphate-dehydrogenase (G6PD) deficiency, XL Xp28 5. Myeloperoxidase deficiency, AR 17q21.3–q23 1268 CHAPTER 22 Primary Immunodeficiencies Table 22.1. (Continued) Classification and inheritance Chromosome Gene defect 6. Specific granule deficiency, AR Xq28 CEBPE 7. Neutropenia a. Cyclic neutropenia 19p13.3 ELA2 b. Congenital neutropenia (Kostmann syndrome) CSF3R 8. Shwachman-Diamond syndrome, AR 7q1.1 9. Leukocyte mycobactericidal defect a. IFN-gR1 deficiency 6q23.q24 IFN-gR1 b. IFN-gR2 deficiency 21q22.1q22.2 IFN-gR2 c. IL12R p40 deficiency 5q31.1-33.1 IL12Rp40 d. IL12Rb1 deficiency 19p13.1 IL12Rb1 IL12Rb1/IL23Rb1 associated deficiency IL12Rb1/IL23b1 STAT deficiency AD STAT STAT deficiency AR STAT F. Complement deficiency 1. C1q deficiency, AR 1p34 C1q 2. C1q/r deficiency, AR 12p13 C1q/2 3. C4 deficiency, AR 6p21.3 C4 4. C2 deficiency, AR 6p21.3 C2 5. C3 deficiency, AR 19p21 C3 6. C5 deficiency, AR 9q32.1 C5 7. C6 deficiency, AR 5q13 C6 8. C7 deficiency, AR 5q13 C7 9. C8 deficiency, AR 1p32 C8 C8a + C8g deficiency, AR 1p34 Ca/g C8l deficiency, AR 9q34 Cl 10. C9 deficiency, AR 5p13 C9 11. C1 inhibitor deficiency, AD 1q p11 12. Factor I deficiency, AR 4q25 13. Factor H deficiency, AR 1q3.2 14. Factor D deficiency, AR 19 15. Properdin deficiency, XL Xp11.4–p11.2 PPC We follow the WHO nomenclature [455], recently updated [351]. Data from [61, 65, 76, 101, 162, 351, 414, 480, 514, 543]. AD autosomal-dominant, ADA adenosine deaminase, ATM ataxia-telangiectasia mutated, AR autosomal-recessive, Btk Bruton’s tyrosine kinase, CIITA class II transactivator, ELA elastase, ID immunodeficiency, JAK Janus-family kinase, PNP purine nucleoside phosphorylase,RAG1 and RAG2 recombination-activating gene-1 and -2,RFX5 regulatory factor X5,TAP-1 and TAP-2 Transporter associated with antigen presentation 1 and 2, WASp Wiskott-Aldrich syndrome protein, XL X linked.