Advertisement

Humoral Primary Immunodeficiency and Autoimmune and Inflammatory Manifestations

  • Aleš Janda
  • Marta Rizzi
Chapter
Part of the Rare Diseases of the Immune System book series (RDIS)

Abstract

A recent extensive analysis encompassing data on more than 2000 patients with PID in French national register revealed that about a quarter of those patients suffer from at least one autoimmune and inflammatory (A/I) conditions. The manifestations spanned through all known A/I symptoms with autoimmune cytopenia being the most frequent one, followed in frequency by gastrointestinal disorders, skin ailments, and rheumatic conditions. About a third of the affected patients did experience more than one A/I manifestation. The relative risk of developing A/I manifestation was 3- to 14-fold higher in patients with PIDs compared to the normal population. The A/I manifestations occurred throughout the life; by the age of 50 years, 40% of the patients were affected.

The treatment of patients presenting with immunodeficiency as well as autoimmunity or chronic inflammation is challenging as it needs to preserve a balance between infection susceptibility and needs for immunosuppression and includes immunoglobulin substitution, steroids, methotrexate, hydroxychloroquine, ciclosporin A or mycophenolate mofetil, rituximab, abatacept, rapamycin, baricitinib, and only in very severe cases hematopoietic stem cell transplantation (HSCT) or gene therapy.

Keywords

Autoimmunity Inflammation Humoral primary immune deficiency Antibody deficiency Therapy 

References

  1. 1.
    Fischer A, Provot J, Jais JP, et al. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol. 2016;140:1388–93.  https://doi.org/10.1016/j.jaci.2016.12.978.CrossRefGoogle Scholar
  2. 2.
    Picard C, Al-Herz W, Bousfiha A, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for primary immunodeficiency 2015. J Clin Immunol. 2015;35:696–726.  https://doi.org/10.1007/s10875-015-0201-1.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Allenspach E, Torgerson TR. Autoimmunity and primary immunodeficiency disorders. J Clin Immunol. 2016;36:57–67.  https://doi.org/10.1007/s10875-016-0294-1.CrossRefPubMedGoogle Scholar
  4. 4.
    Fodil N, Langlais D, Gros P. Primary immunodeficiencies and inflammatory disease: a growing genetic intersection. Trends Immunol. 2016;37:126–40.  https://doi.org/10.1016/j.it.2015.12.006.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Grimbacher B, Warnatz K, Yong PFK, et al. The crossroads of autoimmunity and immunodeficiency: lessons from polygenic traits and monogenic defects. J Allergy Clin Immunol. 2016;137:3–17.  https://doi.org/10.1016/j.jaci.2015.11.004.CrossRefPubMedGoogle Scholar
  6. 6.
    Warnatz K, Voll RE. Pathogenesis of autoimmunity in common variable immunodeficiency. Front Immunol. 2012;3:1–6.  https://doi.org/10.3389/fimmu.2012.00210.CrossRefGoogle Scholar
  7. 7.
    Marciano BE, Holland SM. Primary immunodeficiency diseases: current and emerging therapeutics. Front Immunol. 2017;8:937.  https://doi.org/10.3389/fimmu.2017.00937.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Azizi G, Ziaee V, Tavakol M, et al. Approach to the management of autoimmunity in primary immunodeficiency. Scand J Immunol. 2017;85:13–29.  https://doi.org/10.1016/j.aller.2017.04.004.CrossRefGoogle Scholar
  9. 9.
    Vignesh P, Rawat A, Singh S. An update on the use of immunomodulators in primary immunodeficiencies. Clin Rev Allergy Immunol. 2017;52:287–303.  https://doi.org/10.1007/s12016-016-8591-2.CrossRefPubMedGoogle Scholar
  10. 10.
    Pac MM, Bernatowska EA, Kierkuś J, et al. Gastrointestinal disorders next to respiratory infections as leading symptoms of X-linked agammaglobulinemia in children – 34-year experience of a single center. Arch Med Sci. 2017;2:412–7.  https://doi.org/10.5114/aoms.2016.60338.CrossRefGoogle Scholar
  11. 11.
    Barmettler S, Otani IM, Minhas J, et al. Gastrointestinal manifestations in X-linked Agammaglobulinemia. J Clin Immunol. 2017;37:287–94.  https://doi.org/10.1007/s10875-017-0374-x.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hernandez-Trujillo VP, Scalchunes C, Cunningham-Rundles C, et al. Autoimmunity and inflammation in X-linked agammaglobulinemia. J Clin Immunol. 2014;34:627–32.  https://doi.org/10.1007/s10875-014-0056-x.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    De La Morena M, Haire RN, Ohta Y, et al. Predominance of sterile immunoglobulin transcripts in a female phenotypically resembling Bruton’s agammaglobulinemia. Eur J Immunol. 1995;25:809–15.  https://doi.org/10.1002/eji.1830250327.CrossRefPubMedGoogle Scholar
  14. 14.
    Conley ME, Dobbs AK, Quintana AM, et al. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K. J Exp Med. 2012;209:463–70.  https://doi.org/10.1084/jem.20112533.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Jansen A, van Deuren M, Miller J, et al. Prognosis of Good syndrome: mortality and morbidity of thymoma associated immunodeficiency in perspective. Clin Immunol. 2016;171:12–7.  https://doi.org/10.1016/j.clim.2016.07.025.CrossRefGoogle Scholar
  16. 16.
    Coulter TI, Chandra A, Bacon CM, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study. J Allergy Clin Immunol. 2017;139:597–606.e4.  https://doi.org/10.1016/j.jaci.2016.06.021.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Elkaim E, Neven B, Bruneau J, et al. Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: a cohort study. J Allergy Clin Immunol. 2016;138:210–218.e9.  https://doi.org/10.1016/j.jaci.2016.03.022.CrossRefPubMedGoogle Scholar
  18. 18.
    Buchbinder D, Stinson JR, Nugent DJ, et al. Mild B-cell lymphocytosis in patients with a CARD11 C49Y mutation. J Allergy Clin Immunol. 2015;136:819–821.e1.  https://doi.org/10.1016/j.jaci.2015.03.008.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Brohl AS, Stinson JR, Su HC, et al. Germline CARD11 mutation in a patient with severe congenital B cell lymphocytosis. J Clin Immunol. 2015;35:32–46.  https://doi.org/10.1007/s10875-014-0106-4.CrossRefPubMedGoogle Scholar
  20. 20.
    Snow AL, Xiao W, Stinson JR, et al. Congenital B cell lymphocytosis explained by novel germline CARD11 mutations. J Exp Med. 2012;209:2247–61.  https://doi.org/10.1084/jem.20120831.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Revy P, Muto T, Levy Y, et al. Activation-Induced Cytidine Deaminase (AID) Deficiency Causes the Autosomal Recessive Form of the Hyper-IgM Syndrome (HIGM2). Cell. 2000;102:565–75.  https://doi.org/10.1016/S0092-8674(00)00079-9.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Quartier P, Bustamante J, Sanal O, et al. Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to activation-induced cytidine deaminase deficiency. Clin Immunol. 2004;110:22–9.  https://doi.org/10.1016/j.clim.2003.10.007.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Durandy A, Cantaert T, Kracker S, Meffre E. Potential roles of activation-induced cytidine deaminase in promotion or prevention of autoimmunity in humans. Autoimmunity. 2013;46:148–56.  https://doi.org/10.3109/08916934.2012.750299.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Imai K, Slupphaug G, Lee W-I, et al. Human uracil–DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol. 2003;4:1023–8.  https://doi.org/10.1038/ni974.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Gardes P, Forveille M, Alyanakian M-A, et al. Human MSH6 deficiency is associated with impaired antibody maturation. J Immunol. 2012;188:2023–9.  https://doi.org/10.4049/jimmunol.1102984.CrossRefPubMedGoogle Scholar
  26. 26.
    Rahner N, Höefler G, Högenauer C, et al. Compound heterozygosity for two MSH6 mutations in a patient with early onset colorectal cancer, vitiligo and systemic lupus erythematosus. Am J Med Genet A. 2008;146A:1314–9.  https://doi.org/10.1002/ajmg.a.32210.CrossRefPubMedGoogle Scholar
  27. 27.
    Feuille EJ, Anooshiravani N, Sullivan KE, et al. Autoimmune cytopenias and associated conditions in CVID: a report from the USIDNET registry. J Clin Immunol. 2018;38:28–34.  https://doi.org/10.1007/s10875-017-0456-9.CrossRefPubMedGoogle Scholar
  28. 28.
    Vince N, Boutboul D, Mouillot G, et al. Defects in the CD19 complex predispose to glomerulonephritis, as well as IgG1 subclass deficiency. J Allergy Clin Immunol. 2011;127:538–541.e5.  https://doi.org/10.1016/j.jaci.2010.10.019.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    van Zelm MC, Smet J, Adams B, et al. CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. J Clin Invest. 2010;120:1265–74.  https://doi.org/10.1172/JCI39748.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Salzer U, Bacchelli C, Buckridge S, et al. Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood. 2009;113:1967–76.  https://doi.org/10.1182/blood-2008-02-141937.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Wang H-Y, Ma CA, Zhao Y, et al. Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK. Proc Natl Acad Sci. 2013;110:5127–32.  https://doi.org/10.1073/pnas.1221211110.CrossRefPubMedGoogle Scholar
  32. 32.
    Chen K, Coonrod EM, Kumánovics A, et al. Germline mutations in NFKB2 implicate the noncanonical NF-κB pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet. 2013;93:812–24.  https://doi.org/10.1016/j.ajhg.2013.09.009.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Villa A, Notarangelo LD, Roifman CM. Omenn syndrome: inflammation in leaky severe combined immunodeficiency. J Allergy Clin Immunol. 2008;122:1082–6.  https://doi.org/10.1016/j.jaci.2008.09.037.CrossRefPubMedGoogle Scholar
  34. 34.
    Niehues T, Perez-Becker R, Schuetz C. More than just SCID—the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. Clin Immunol. 2010;135:183–92.  https://doi.org/10.1016/j.clim.2010.01.013.CrossRefPubMedGoogle Scholar
  35. 35.
    Patel K, Akhter J, Kobrynski L, et al. Immunoglobulin deficiencies: the B-lymphocyte side of DiGeorge syndrome. J Pediatr. 2012;161:950–3.  https://doi.org/10.1016/j.jpeds.2012.06.018.CrossRefGoogle Scholar
  36. 36.
    McLean-Tooke A, Spickett GP, Gennery AR. Immunodeficiency and autoimmunity in 22q11.2 deletion syndrome. Scand J Immunol. 2007;66:1–7.  https://doi.org/10.1111/j.1365-3083.2007.01949.x.CrossRefPubMedGoogle Scholar
  37. 37.
    Candotti F. Clinical manifestations and pathophysiological mechanisms of the Wiskott-Aldrich syndrome. J Clin Immunol. 2018;38:13–27.  https://doi.org/10.1007/s10875-017-0453-z.CrossRefPubMedGoogle Scholar
  38. 38.
    Massaad MJ, Ramesh N, Geha RS. Wiskott-Aldrich syndrome: a comprehensive review. Ann N Y Acad Sci. 2013;1285:26–43.  https://doi.org/10.1111/nyas.12049.CrossRefPubMedGoogle Scholar
  39. 39.
    Burns SO, Zarafov A, Thrasher AJ. Primary immunodeficiencies due to abnormalities of the actin cytoskeleton. Curr Opin Hematol. 2017;24:16–22.  https://doi.org/10.1097/MOH.0000000000000296.CrossRefPubMedGoogle Scholar
  40. 40.
    Dobbs K, Domínguez Conde C, Zhang S-Y, et al. Inherited DOCK2 deficiency in patients with early-onset invasive infections. N Engl J Med. 2015;372:2409–22.  https://doi.org/10.1056/NEJMoa1413462.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Biggs CM, Keles S, Chatila TA. DOCK8 deficiency: insights into pathophysiology, clinical features and management. Clin Immunol. 2017;181:75–82.  https://doi.org/10.1016/j.clim.2017.06.003.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Stepensky P, Keller B, Buchta M, et al. Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects. J Allergy Clin Immunol. 2013;131:477–485.e1.  https://doi.org/10.1016/j.jaci.2012.11.050.CrossRefPubMedGoogle Scholar
  43. 43.
    Dadi H, Jones TA, Merico D, et al. Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11). J Allergy Clin Immunol. 2017;141:1818.  https://doi.org/10.1016/j.jaci.2017.06.047.CrossRefPubMedGoogle Scholar
  44. 44.
    Feyder M, Goff L. Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity. J Clin Invest. 2014;124:5239–48.  https://doi.org/10.1172/JCI77493.CrossRefGoogle Scholar
  45. 45.
    Fusco F, Pescatore A, Conte MI, et al. EDA-ID and IP, two faces of the same coin: how the same IKBKG/NEMO mutation affecting the NF-κB pathway can cause immunodeficiency and/or inflammation. Int Rev Immunol. 2015;34:445–59.  https://doi.org/10.3109/08830185.2015.1055331.CrossRefPubMedGoogle Scholar
  46. 46.
    Petersheim D, Massaad MJ, Lee S, et al. Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency canonical NF-κB pathway non-canonical NF-κB pathway. J Allergy Clin Immunol. 2017;141:1060.  https://doi.org/10.1016/j.jaci.2017.05.030.CrossRefPubMedGoogle Scholar
  47. 47.
    Boisson B, Puel A, Picard C, Casanova JL. Human IκBα gain of function: a severe and syndromic immunodeficiency. J Clin Immunol. 2017;37:397–412.  https://doi.org/10.1007/s10875-017-0400-z.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Willmann KL, Klaver S, Do UF, et al. Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity. Nat Commun. 2014;5:5360.  https://doi.org/10.1038/ncomms6360.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Salzer E, Santos-Valente E, Keller B, et al. Protein kinase C δ: a gatekeeper of immune homeostasis. J Clin Immunol. 2016;36:631–40.  https://doi.org/10.1007/s10875-016-0323-0.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Jesus AA, Duarte AJS, Oliveira JB. Autoimmunity in hyper-IgM syndrome. J Clin Immunol. 2008;28:62–6.  https://doi.org/10.1007/s10875-008-9171-x.CrossRefGoogle Scholar
  51. 51.
    Schepp J, Chou J, Skrabl-Baumgartner A, et al. 14 years after discovery: clinical follow-up on 15 patients with inducible co-stimulator deficiency. Front Immunol. 2017;8:964.  https://doi.org/10.3389/fimmu.2017.00964.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Tangye SG. XLP: clinical features and molecular etiology due to mutations in SH2D1A encoding SAP. J Clin Immunol. 2014;34:772–9.  https://doi.org/10.1007/s10875-014-0083-7.CrossRefPubMedGoogle Scholar
  53. 53.
    Aguilar C, Latour S. X-linked inhibitor of apoptosis protein deficiency: more than an X-linked lymphoproliferative syndrome. J Clin Immunol. 2015;35:331–8.  https://doi.org/10.1007/s10875-015-0141-9.CrossRefPubMedGoogle Scholar
  54. 54.
    Verma N, Burns SO, Walker LSK, Sansom DM. Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations. Clin Exp Immunol. 2017;190:1–7.  https://doi.org/10.1111/cei.12997.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Gámez-Díaz L, August D, Stepensky P, et al. The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. J Allergy Clin Immunol. 2016;137:223–30.  https://doi.org/10.1016/j.jaci.2015.09.025.CrossRefPubMedGoogle Scholar
  56. 56.
    Alkhairy OK, Perez-Becker R, Driessen GJ, et al. Novel mutations in TNFRSF7/CD27: clinical, immunologic, and genetic characterization of human CD27 deficiency. J Allergy Clin Immunol. 2015;136:703–712.e10.  https://doi.org/10.1016/j.jaci.2015.02.022.CrossRefPubMedGoogle Scholar
  57. 57.
    Salzer E, Kansu A, Sic H, et al. Early-onset inflammatory bowel disease and common variable immunodeficiency–like disease caused by IL-21 deficiency. J Allergy Clin Immunol. 2014;133:1651–1659.e12.  https://doi.org/10.1016/j.jaci.2014.02.034.CrossRefPubMedGoogle Scholar
  58. 58.
    Kotlarz D, Ziętara N, Milner JD, Klein C. Human IL-21 and IL-21R deficiencies. Curr Opin Pediatr. 2014;26:704–12.  https://doi.org/10.1097/MOP.0000000000000160.CrossRefPubMedGoogle Scholar
  59. 59.
    Kotlarz D, Ziętara N, Uzel G, et al. Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome. J Exp Med. 2013;210:433–43.  https://doi.org/10.1084/jem.20111229.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    De Bruin AM, Voermans C, Nolte MA. Impact of interferon-g on hematopoiesis. Blood. 2014;124:2479–86.  https://doi.org/10.1182/blood-2014-04.CrossRefPubMedGoogle Scholar
  61. 61.
    Lorenzini T, Dotta L, Giacomelli M, et al. STAT mutations as program switchers: turning primary immunodeficiencies into autoimmune diseases. J Leukoc Biol. 2017;101:29–38.  https://doi.org/10.1189/jlb.5RI0516-237RR.CrossRefPubMedGoogle Scholar
  62. 62.
    Bride K, Teachey D. Autoimmune lymphoproliferative syndrome: more than a FAScinating disease. F1000Research. 2017;6:1928.  https://doi.org/10.12688/f1000research.11545.1.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Faculty of Medicine, Centre for PaediatricsMedical Center - University of FreiburgFreiburg im BreisgauGermany
  2. 2.Faculty of Medicine, Department of Rheumatology and Clinical Immunology and Center for Chronic ImmunodeficiencyMedical Center-University of FreiburgFreiburg im BreisgauGermany

Personalised recommendations