Selective immunoglobulin A deficiency

1. Selective Immunoglobulin A Deficiency Yoavanit Srivaro M.D.

2. Outlines •Introduction •Immunoglobulin A and Its Functions •Pathogenesis •Epidemiology •Clinical Manifestations •Laboratory Evaluation •Management •Prognosis

3. Introduction

4. Benjasupattananan P, Simasathein T, Vichyanond P, Leungwedchakarn V, Visitsunthorn N, Pacharn P, et al. Clinical characteristics and outcomes of primary immunodeficiencies in Thai children: an 18-year experience from a tertiary care center. Journal of clinical immunology. 2009;29:357-64.

5. Benjasupattananan P, Simasathein T, Vichyanond P, Leungwedchakarn V, Visitsunthorn N, Pacharn P, et al. Clinical characteristics and outcomes of primary immunodeficiencies in Thai children: an 18-year experience from a tertiary care center. Journal of clinical immunology. 2009;29:357-64.

6. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and

7. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and Serum Immunoglobulin Assay : IgG,IgA,IgM

8. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and Serum Immunoglobulin Assay : IgG,IgA,IgM IgG,IgA and/or IgM

9. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and Serum Immunoglobulin Assay : IgG,IgA,IgM IgG,IgA and/or IgM B lymphocyte CD 19+

10. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and Serum Immunoglobulin Assay : IgG,IgA,IgM IgG,IgA and/or IgM B lymphocyte CD 19+ CD 19+ absent X-Linked Agammaglobulinemia

11. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and Serum Immunoglobulin Assay : IgG,IgA,IgM IgG,IgA and/or IgM B lymphocyte CD 19+ CD 19+ absent X-Linked Agammaglobulinemia CD 19+ >1% CVID

12. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and Serum Immunoglobulin Assay : IgG,IgA,IgM IgG,IgA and/or IgM B lymphocyte CD 19+ CD 19+ absent X-Linked Agammaglobulinemia CD 19+ >1% CVID IgG and IgA and normal or IgM

13. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and Serum Immunoglobulin Assay : IgG,IgA,IgM IgG,IgA and/or IgM B lymphocyte CD 19+ CD 19+ absent X-Linked Agammaglobulinemia CD 19+ >1% CVID IgG and IgA and normal or IgM Transient hypogammaglo -bulinemia of infancy

14. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and Serum Immunoglobulin Assay : IgG,IgA,IgM IgG,IgA and/or IgM B lymphocyte CD 19+ CD 19+ absent X-Linked Agammaglobulinemia CD 19+ >1% CVID IgG and IgA and normal or IgM Transient hypogammaglo -bulinemia of infancy

15. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and Serum Immunoglobulin Assay : IgG,IgA,IgM IgG,IgA and/or IgM B lymphocyte CD 19+ CD 19+ absent X-Linked Agammaglobulinemia CD 19+ >1% CVID IgG and IgA and normal or IgM Transient hypogammaglo -bulinemia of infancy HyperIgM syndrome

16. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Serum Immunoglobulin Assay : IgG,IgA,IgM IgG,IgA and/or IgM IgG and IgA and normal or IgM Normal IgG,IgA,IgM B lymphocyte CD 19+ CD 19+ absent CD 19+ >1% X-Linked Agammaglobulinemia CVID HyperIgM syndrome Transient hypogammaglo -bulinemia of infancy Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and

17. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Serum Immunoglobulin Assay : IgG,IgA,IgM IgG,IgA and/or IgM IgG and IgA and normal or IgM Normal IgG,IgA,IgM B lymphocyte CD 19+ CD 19+ absent CD 19+ >1% X-Linked Agammaglobulinemia CVID HyperIgM syndrome Transient hypogammaglo -bulinemia of infancy Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and Abn Specific Ab resonse to vaccine Specific Ab def.

18. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and Serum Immunoglobulin Assay : IgG,IgA,IgM IgG,IgA and/or IgM B lymphocyte CD 19+ CD 19+ absent X-Linked Agammaglobulinemia CD 19+ >1% CVID IgG and IgA and normal or IgM Transient hypogammaglo -bulinemia of infancy HyperIgM syndrome IgA Normal IgG,IgA,IgM Abn Specific Ab resonse to vaccine Specific Ab def.

19. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Serum Immunoglobulin Assay : IgG,IgA,IgM IgG,IgA and/or IgM IgG and IgA and normal or IgM IgA Normal IgG,IgA,IgM B lymphocyte CD 19+ CD 19+ absent CD 19+ >1% X-Linked Agammaglobulinemia CVID HyperIgM syndrome Transient hypogammaglo -bulinemia of infancy Specific Ab resonse to vaccine Abn Specific Ab resonse to vaccine Specific Ab def. Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and

20. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Serum Immunoglobulin Assay : IgG,IgA,IgM IgG,IgA and/or IgM IgG and IgA and normal or IgM IgA Normal IgG,IgA,IgM B lymphocyte CD 19+ CD 19+ absent CD 19+ >1% X-Linked Agammaglobulinemia CVID HyperIgM syndrome Transient hypogammaglo -bulinemia of infancy Specific Ab resonse to vaccine Abn Specific Ab resonse to vaccine Specific Ab def. Low Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and

21. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Serum Immunoglobulin Assay : IgG,IgA,IgM IgG,IgA and/or IgM IgG and IgA and normal or IgM IgA Normal IgG,IgA,IgM B lymphocyte CD 19+ CD 19+ absent CD 19+ >1% X-Linked Agammaglobulinemia CVID HyperIgM syndrome Transient hypogammaglo -bulinemia of infancy Specific Ab resonse to vaccine IgA with Specific Ab def. Abn Specific Ab resonse to vaccine Specific Ab def. Low Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and

22. Predominantly antibody deficiency Recurrent bacterial infection :Otitis,Pneumonia,Sinusitis,Diarrhea,Sepsis Serum Immunoglobulin Assay : IgG,IgA,IgM IgG,IgA and/or IgM IgG and IgA and normal or IgM IgA Normal IgG,IgA,IgM B lymphocyte CD 19+ CD 19+ absent CD 19+ >1% X-Linked Agammaglobulinemia CVID HyperIgM syndrome Transient hypogammaglo -bulinemia of infancy Specific Ab resonse to vaccine Selective IgA def. IgA with Specific Ab def. Abn Specific Ab resonse to vaccine Specific Ab def. Normal Low Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and

23. Selective IgA Deficiency “First described in 1964” Rockey JH, Hanson LA, Heremans JF, Kunkel HG. BETA-2A AGLOBULINEMIA IN TWO HEALTHY MEN. The Journal of laboratory and clinical medicine. 1964;63:205-12.

24. Rockey JH, Hanson LA, Heremans JF, Kunkel HG. BETA-2A AGLOBULINEMIA IN TWO HEALTHY MEN. The Journal of laboratory and clinical medicine. 1964;63:205-12.

25. Definition •Male or female greater than 4 years of age •Serum IgA of less than 7 mg/dL (0.07 g/L) •Normal serum IgG and IgM •Other causes of hypogammaglobulinemia have been excluded •Normal IgG antibody response to vaccination Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clinical immunology (Orlando, Fla). 1999;93:190-7. Ballas ZK, Chinen J, Frank MM, Hsu JT, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. The Journal of allergy and clinical immunology. 2015.

26. Definition •Male or female greater than 4 years of age •Serum IgA of less than 7 mg/dL (0.07 g/L) •Normal serum IgG and IgM •Other causes of hypogammaglobulinemia have been excluded •Normal IgG antibody response to vaccination Ballas ZK, Chinen J, Frank MM, Hsu JT, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. The Journal of allergy and clinical immunology. 2015. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clinical immunology (Orlando, Fla). 1999;93:190-7.

30. Partial Ig A Deficiency •Male or female greater than 4 years of age •Serum IgA at least 2 SD below normal for age •Normal serum IgG and IgM Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clinical immunology (Orlando, Fla). 1999;93:190-7.

31. Immunoglobulin A And Its Functions

32. Immunoglobulin A “First described in serum in 1953” Grabar P, Williams CA. [Method permitting the combined study of the electrophoretic and the immunochemical properties of protein mixtures; application to blood serum]. Biochimica et biophysica acta.

33. Distribution •Most abundant antibody isotypes •60-70% of total production of antibodies •Majority of IgA 1.Mucous secretion :Saliva,Milk,Colostrum,Tears 2.Secretion from :Respiratory tract ,Genitourinary tract ,Prostate Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015. Woof JM, Kerr MA. The function of immunoglobulin A in immunity. The Journal of pathology. 2006;208(2):270-82.

34. Normal Serum Level •IgA is the second most abundant isotype in the circulation. •Range from 61 to 356 mg/dL. Woof JM, Kerr MA. The function of immunoglobulin A in immunity. The Journal of pathology. 2006;208(2):270-82.

35. Jolliff CR, Cost KM, Stivrins PC, Grossman PP, Nolte CR, Franco SM, et al. Reference intervals for serum IgG, IgA, IgM, C3, and C4 as determined by rate nephelometry. Clinical chemistry. 1982;28:126-8.

36. Figure 3-7 Basic structure of immunoglobulin molecules. Jelinek DF,Li JT.Immunoglobulin Structure and Function In: Adkinson NF,Bochner BS, Burks AW, Busse WW,Holgate ST, Lemanske RF, O’Hehir RE, editors. Middleton’s allergy: principles & practice. 8 th ed. Philadelphia: Mosby-Elsevier; 2014. p.30-44.

39. Figure 1. Human IgA structure. Woof JM, Russell MW. Structure and function relationships in IgA. Mucosal immunology. 2011;4:590-7.

40. Woof JM, Russell MW. Structure and function relationships in IgA. Mucosal immunology. 2011;4:590-7. Figure 1. Human IgA structure.

41. Woof JM, Russell MW. Structure and function relationships in IgA. Mucosal immunology. 2011;4:590-7. Figure 1. Human IgA structure.

42. Figure 3-7 Basic structure of immunoglobulin molecules. Jelinek DF,Li JT.Immunoglobulin Structure and Function In: Adkinson NF,Bochner BS, Burks AW, Busse WW,Holgate ST, Lemanske RF, O’Hehir RE, editors. Middleton’s allergy: principles & practice. 8 th ed. Philadelphia: Mosby-Elsevier; 2014. p.30-44. Monomeric Serum IgA

43. Dimeric form IgA Woof JM, Russell MW. Structure and function relationships in IgA. Mucosal immunology. 2011;4:590-7. Figure 1. Human IgA structure.

44. Dimeric form IgA Woof JM, Russell MW. Structure and function relationships in IgA. Mucosal immunology. 2011;4:590-7. Figure 1. Human IgA structure.

45. Figure 3-7 Basic structure of immunoglobulin molecules. Jelinek DF,Li JT.Immunoglobulin Structure and Function In: Adkinson NF,Bochner BS, Burks AW, Busse WW,Holgate ST, Lemanske RF, O’Hehir RE, editors. Middleton’s allergy: principles & practice. 8 th ed. Philadelphia: Mosby-Elsevier; 2014. p.30-44. Dimeric form IgA

46. Figure 3-7 Basic structure of immunoglobulin molecules. Jelinek DF,Li JT.Immunoglobulin Structure and Function In: Adkinson NF,Bochner BS, Burks AW, Busse WW,Holgate ST, Lemanske RF, O’Hehir RE, editors. Middleton’s allergy: principles & practice. 8 th ed. Philadelphia: Mosby-Elsevier; 2014. p.30-44. Dimeric form IgA

47. Production From Plasma cell in Bone marrow From Locally in the mucosal tissue Woof JM, Kerr MA. The function of immunoglobulin A in immunity. The Journal of pathology. 2006;208:270-82. Serum IgA

48. Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015. Jelinek DF,Li JT.Immunoglobulin Structure and Function In: Adkinson NF,Bochner BS,Burks AW,Busse WW,Holgate ST, Lemanske RF, O’Hehir RE, editors. Middleton’s allergy: principles & practice. 8 th ed. Philadelphia: Mosby-Elsevier; 2014. p.30-44. Figure 3-8 Germline organization of human immunoglobulin gene loci.

49. Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015. Jelinek DF,Li JT.Immunoglobulin Structure and Function In: Adkinson NF,Bochner BS,Burks AW,Busse WW,Holgate ST, Lemanske RF, O’Hehir RE, editors. Middleton’s allergy: principles & practice. 8 th ed. Philadelphia: Mosby-Elsevier; 2014. p.30-44. Figure 3-8 Germline organization of human immunoglobulin gene loci.

50. Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015. FIGURE 14-7 A IgA class switching in the gut. T-dependent IgA class switching

59. Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015. FIGURE 14-7 B IgA class switching in the gut. T-independent IgA class switching

64. Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015. FIGURE 14-8 Transport of IgA across epithelial cells.

70. FIGURE 3-11 Fc receptor expression pattern on human cells and biologic activity. Jelinek DF,Li JT.Immunoglobulin Structure and Function In: Adkinson NF,Bochner BS, Burks AW,Busse WW,Holgate ST, Lemanske RF, O’Hehir RE, editors. Middleton’s allergy: principles & practice. 8 th ed. Philadelphia: Mosby-Elsevier; 2014. p.30-44.

71. Fig. 1 a Schematic representation of immunoglobulin A (IgA) binding to the Fc alpha RI–FcR gammachain Mkaddem SB, Christou I, Rossato E, Berthelot L, Lehuen A, Monteiro RC.In IgA, IgA receptors, and their anti- inflammatory properties In : Daëron M, Nimmerjahn F,editors :Current Topics in Microbiology and Immunology . 1st ed. Switzerland Springer International Publishing; 2014. p221-35 .

72. Fig. 2 Simplified scheme of Fc alpha RI signaling pathways Mkaddem SB, Christou I, Rossato E, Berthelot L, Lehuen A, Monteiro RC.In IgA, IgA receptors, and their anti- inflammatory properties In : Daëron M, Nimmerjahn F,editors :Current Topics in Microbiology and Immunology . 1st ed. Switzerland Springer International Publishing; 2014. p221-35 . Activation

73. Mkaddem SB, Christou I, Rossato E, Berthelot L, Lehuen A, Monteiro RC.In IgA, IgA receptors, and their anti- inflammatory properties In : Daëron M, Nimmerjahn F,editors :Current Topics in Microbiology and Immunology . 1st ed. Switzerland Springer International Publishing; 2014. p221-35 . Inhibition Fig. 1 a Schematic representation of immunoglobulin A (IgA) binding to the Fc alpha RI–FcRc-chain

74. Fig. 1 b DC-SIGN/SIGNR1 and secretory IgA (SIgA) representation Mkaddem SB, Christou I, Rossato E, Berthelot L, Lehuen A, Monteiro RC.In IgA, IgA receptors, and their anti- inflammatory properties In : Daëron M, Nimmerjahn F,editors :Current Topics in Microbiology and Immunology . 1st ed. Switzerland Springer International Publishing; 2014. p221-35 . Regulatory Function

75. Jelinek DF,Li JT.Immunoglobulin Structure and Function In: Adkinson NF,Bochner BS, Burks AW, Busse WW,Holgate ST, Lemanske RF, O’Hehir RE, editors. Middleton’s allergy: principles & practice. 8 th ed. Philadelphia: Mosby-Elsevier; 2014. p.30-44.

78. Pathogenesis

79. Stem Cells Defect Yel L. Selective IgA deficiency. Journal of clinical immunology. 2010;30:10-6

80. Hammarstrom L, Lonnqvist B, Ringden O, Smith CI, Wiebe T. Transfer of IgA deficiency to a bone-marrow- grafted patient with aplastic anaemia. Lancet (London, England). 1985;1:778-81.

81. Hammarstrom L, Lonnqvist B, Ringden O, Smith CI, Wiebe T. Transfer of IgA deficiency to a bone-marrow- grafted patient with aplastic anaemia. Lancet (London, England). 1985;1:778-81.

82. Block in differentiation of B cells to IgA antibody secreting plasma cell Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015.

83. FIG. 1. Overview of B-cell development and defects causing antibody deficiency. Fried AJ, Bonilla FA. Pathogenesis, diagnosis, and management of primary antibody deficiencies and infections. Clinical microbiology reviews. 2009;22:396-414.

84. Nechvatalova J, Pikulova Z, Stikarovska D, Pesak S, Vlkova M, Litzman J. B-lymphocyte subpopulations in patients with selective IgA deficiency. Journal of clinical immunology. 2012;32(3):441-8.

85. Alpha heavy chain gene deletions involving various segments on chromosome 14

86. Suzuki H, Kaneko H, Fukao T, Jin R, Kawamoto N, Asano T, et al. Various expression patterns of alpha1 and alpha2 genes in IgA deficiency. Allergology international : official journal of the Japanese Society of Allergology. 2009;58:111-7.

87. Suzuki H, Kaneko H, Fukao T, Jin R, Kawamoto N, Asano T, et al. Various expression patterns of alpha1 and alpha2 genes in IgA deficiency. Allergology international : official journal of the Japanese Society of Allergology. 2009;58:111-7.

88. TACI and BAFFR gene Abnormality

89. Rachid R, Castigli E, Geha RS, Bonilla FA. TACI mutation in common variable immunodeficiency and IgA deficiency. Current allergy and asthma reports. 2006;6:357-62.

90. Abnormality of The Cytokine network Cunningham-Rundles C. Physiology of IgA and IgA deficiency. JClin Immunol. 2001;21:303–9.

91. • IL-4 • IL-6 • IL-7 • IL-10 • TGF-β • IL-21 Cunningham-Rundles C. Physiology of IgA and IgA deficiency. JClin Immunol. 2001;21:303–9.

92. Genetic

93. MHC loci associations

94. The 8.1 Haplotype MHC Haplotype A1,B8,DR3,DQ2 Wikipedia. HLA A1-B8-DR3-DQ2 [Internet]. 2015 [cited 2015 Sep 19]. Available from: http://en.wikipedia.org/wiki/HLA A1-B8-DR3-DQ2

95. The 8.1 Haplotype MHC Haplotype A1,B8,DR3,DQ2 IgA deficiency Patients Healthy polpulation 45% 16% Singh K, Chang C, Gershwin ME. IgA deficiency and autoimmunity. Autoimmunity reviews. 2014;13:163-77.

96. Mohammadi J, Ramanujam R, Jarefors S, Rezaei N, Aghamohammadi A, Gregersen PK, et al. IgA deficiency and the MHC: assessment of relative risk and microheterogeneity within the HLA A1 B8, DR3 (8.1) haplotype. Journal of clinical immunology. 2010;30:138-43.

97. Abnormalities in genes associated with autoimmunity

98. IF1H1 =Interferon induced with helicase C domain 1 protein Ferreira RC, Pan-Hammarstrom Q, Graham RR, Gateva V, Fontan G, Lee AT, et al. Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency. Nature genetics. 2010;42(9):777-80.

99. Wang N, Shen N, Vyse TJ, Anand V, Gunnarson I, Sturfelt G, et al. Selective IgA deficiency in autoimmune diseases. Molecular medicine (Cambridge, Mass). 2011;17(11-12):1383-96.

100. CLEC 16 A =C-type lectin domain family 16 Ferreira RC, Pan-Hammarstrom Q, Graham RR, Gateva V, Fontan G, Lee AT, et al. Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency. Nature genetics. 2010;42(9):777-80.

101. Wang N, Shen N, Vyse TJ, Anand V, Gunnarson I, Sturfelt G, et al. Selective IgA deficiency in autoimmune diseases. Molecular medicine (Cambridge, Mass). 2011;17(11-12):1383-96.

102. 18q deletion syndrome Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. The Journal of allergy and clinical immunology. 2015.

103. IgG4 deficiency Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. The Journal of allergy and clinical immunology. 2015.

104. Epidemiology

105. IgA deficiency is more common in Caucasians. Yel L. Selective IgA deficiency. Journal of clinical immunology. 2010;30:10-6

106. Country Prevalence Arabian peninsula 1:143 Spain 1:163 Nigeria 1:252 England 1:875 Brazil 1:965 USA 1:223 to 1:1,000 China 1:2,600 to 1:5,300 Japan 1:14,840 to 1:18,500 Yel L. Selective IgA deficiency. Journal of clinical immunology. 2010;30:10-6

107. Phankingthongkum S, Visitsunthorn N, Vichyanond P. IgA deficiency: a report of three cases from Thailand. Asian Pacific journal of allergy and immunology / launched by the Allergy and Immunology Society of Thailand. 2002;20:203-7.

108. Clinical Manifestations

109. Wide spectrum of clinical findings • Asymtomatic • Recurrent sinopulmonary infections • Gastrointestinal infections and disorders • Allergic disorder • Autoimmune conditions • Malignancies Yel L. Selective IgA deficiency. Journal of clinical immunology. 2010;30:10-6

110. Edwards E, Razvi S, Cunningham-Rundles C. IgA deficiency: clinical correlates and responses to pneumococcal vaccine. Clinical immunology (Orlando, Fla). 2004;111:93-7.

115. Recurrent sinopulmonary infections Edwards E, Razvi S, Cunningham-Rundles C. IgA deficiency: clinical correlates and responses to pneumococcal vaccine. Clinical immunology (Orlando, Fla). 2004;111:93-7.

116. Aghamohammadi A, Cheraghi T, Gharagozlou M, Movahedi M, Rezaei N, Yeganeh M, et al. IgA deficiency: correlation between clinical and immunological phenotypes. Journal of clinical immunology. 2009;29:130-6.

117. Chipps BE, Talamo RC, Winkelstein JA. IgA deficiency, recurrent pneumonias, and bronchiectasis. Chest. 1978;73:519-26.

118. Chipps BE, Talamo RC, Winkelstein JA. IgA deficiency, recurrent pneumonias, and bronchiectasis. Chest.

119. Gastrointestinal infections and disorders •Giardia lamblia •Malabsorption •Celiac disease •Ulcerative colitis •Nodular lymphoid hyperpalsia Yel L. Selective IgA deficiency. Journal of clinical immunology. 2010;30:10-6

121. Eren M, Saltik-Temizel IN, Yuce A, Caglar M, Kocak N. Duodenal appearance of giardiasis in a child with selective immunoglobulin A deficiency. Pediatrics international : official journal of the Japan Pediatric

122. Eren M, Saltik-Temizel IN, Yuce A, Caglar M, Kocak N. Duodenal appearance of giardiasis in a child with selective immunoglobulin A deficiency Pediatrics international : official journal of the Japan Pediatric Society. 2007;49(3):409-11

125. Figure 1 Endoscopic appearance of nodular lymphoid hyperplasia. • In immunodeficiency states • To compensate functional inadequate intestinal lymphoid tissue. • NLH result from an accumulation of plasma- cell precursors. Albuquerque A. Nodular lymphoid hyperplasia in the gastrointestinal tract in adult patients: A review. World journal of gastrointestinal endoscopy. 2014;6:534-40.

126. Allergic disorder Edwards E, Razvi S, Cunningham-Rundles C. IgA deficiency: clinical correlates and responses to pneumococcal vaccine. Clinical immunology (Orlando, Fla). 2004;111:93-7.

128. Autoimmune conditions •This figure varies from 3.3 % to 33.6 %based on the age range of studied populations . Singh K, Chang C, Gershwin ME. IgA deficiency and autoimmunity. Autoimmunity reviews. 2014;13:163-77.

129. Why IgA deficiency may be associated with autoimmunity? •Genetic factor : HLA haplotypes 8.1 •Ig A protect against immunity :IgA interaction with FCR alpha RI •Anti-bovine immunoprecipitins in IgA def. pt. Singh K, Chang C, Gershwin ME. IgA deficiency and autoimmunity. Autoimmunity reviews. 2014;13:163-77.

132. Mkaddem SB, Christou I, Rossato E, Berthelot L, Lehuen A, Monteiro RC.In IgA, IgA receptors, and their anti- inflammatory properties In : Daëron M, Nimmerjahn F,editors :Current Topics in Microbiology and Immunology . 1st ed. Switzerland Springer International Publishing; 2014. p221-35 . Inhibition Fig. 1 a Schematic representation of immunoglobulin A (IgA) binding to the Fc alpha RI–FcRc-chain

134. Autoimmune conditions Edwards E, Razvi S, Cunningham-Rundles C. IgA deficiency: clinical correlates and responses to pneumococcal vaccine. Clinical immunology (Orlando, Fla). 2004;111:93-7.

137. Wang N, Shen N, Vyse TJ, Anand V, Gunnarson I, Sturfelt G, et al. Selective IgA deficiency in autoimmune diseases. Molecular medicine (Cambridge, Mass). 2011;17:1383-96.

143. Celiac Disease Fasano A, Catassi C. Clinical practice. Celiac disease. The New England journal of medicine. 2012;367:2419-26.

144. Celiac Disease Fasano A, Catassi C. Clinical practice. Celiac disease. The New England journal of medicine. 2012;367:2419-26.

145. Anti IgA antibody Feng ML, Zhao YL, Shen T, Huang H, Yin B, Liu RZ, et al. Prevalence of immunoglobulin A deficiency in Chinese blood donors and evaluation of anaphylactic transfusion reaction risk. Transfusion medicine (Oxford, England). 2011;21:338-43.

146. Malignancies Edwards E, Razvi S, Cunningham-Rundles C. IgA deficiency: clinical correlates and responses to pneumococcal vaccine. Clinical immunology (Orlando, Fla). 2004;111:93-7.

147. Table 2 Malignancies and person-years Ludvigsson JF, Neovius M, Ye W, Hammarstrom L. IgA deficiency and risk of cancer: a population-based matched cohort study. Journal of clinical immunology. 2015;35:182-8.

150. Fig. 1 Malignancies in IgAD (IgA deficiency) patients and matched general population comparators over 25 years of follow-up • During follow-up • 125 pts with IgA def. (61/10,000 person-years) • 984 controls (47/10,000 person-years) • Developed cancer • HR 1.31; 95%CI = 1.09-1.58 Ludvigsson JF, Neovius M, Ye W, Hammarstrom L. IgA deficiency and risk of cancer: a population-based matched cohort study. Journal of clinical immunology. 2015;35:182-8.

151. Table 2 Malignancies and person-years :Conditional hazard ratio Ludvigsson JF, Neovius M, Ye W, Hammarstrom L. IgA deficiency and risk of cancer: a population-based matched cohort study. Journal of clinical immunology. 2015;35:182-8.

152. Laboratory Evaluation

153. IgA deficiency should be a consideration in a patient with…? •Recurrent respiratory infections •Recurrent gastrointestinal infections •Allergic disorders •Autoimmune disorders Yel L. Selective IgA deficiency. Journal of clinical immunology. 2010;30:10-6.

154. Immunologic evaluation for IgA deficiency is also warranted in…? •Case of anaphylaxis secondary to a blood product transfusion •Celiac disease •Family history of IgA deficiency and/or CVID. Yel L. Selective IgA deficiency. Journal of clinical immunology. 2010;30:10-6.

155. Hammarstrom L, Vorechovsky I, Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clinical and experimental immunology. 2000;120:225-31.

156. Evaluation of a suspected IgA deficiency •Complete blood count •Quantitative serum immunoglobulin levels •Serum IgG subclasses •Specific antibody response to protein & polysaccharide antigens •Lymphocyte subsets Yel L. Selective IgA deficiency. Journal of clinical immunology. 2010;30:10-6.

158. Management

159. Asymptomatic IgA deficiency 1. Do not need any treatment 2. Awareness & Education to prevent anaphylactic reaction from blood transfusion 2.1 Wear a medical alert bracelet 2.2 Receive washed normal donor erythrocytes or blood product from IgA def. person Yel L. Selective IgA deficiency. Journal of clinical immunology. 2010;30:10-6. Buckley RH,Orange JS. Primary Immunodeficiency Diseases In: Adkinson NF,Bochner BS, Burks AW, Busse WW,Holgate ST, Lemanske RF, O’Hehir RE, editors. Middleton’s allergy: principles & practice. 8 th ed. Philadelphia: Mosby-Elsevier; 2014. p.1144-74.

160. Asymptomatic IgA deficiency 1. Do not need any treatment 2. Awareness & Education to prevent anaphylactic reaction from blood transfusion 2.1 Wear a medical alert bracelet 2.2 Receive washed normal donor erythrocytes or blood product from IgA def. person Yel L. Selective IgA deficiency. Journal of clinical immunology. 2010;30:10-6. Buckley RH,Orange JS. Primary Immunodeficiency Diseases In: Adkinson NF,Bochner BS, Burks AW, Busse WW,Holgate ST, Lemanske RF, O’Hehir RE, editors. Middleton’s allergy: principles & practice. 8 th ed. Philadelphia: Mosby-Elsevier; 2014. p.1144-74.

161. • The patient has sIgAD • The patient is at risk for an allergic reaction to any injected plasma-containing blood products & testing for anti-IgA antibodies should be performed before such blood products are administered. Medical Alert Bracelet

162. • 19-year-old woman • End-stage Type 2 autoimmune hepatitis required liver transplantation • She also had sIgAD, anti-IgA antibodies • Episodes of anaphylaxis after receiving IgA-containing blood products • Plan tx with Liver transplantation Kiani-Alikhan S, Yong PF, Grosse-Kreul D, Height SE, Mijovic A, Suddle AR, et al. Successful desensitization to immunoglobulin A in a case of transfusion-related anaphylaxis. Transfusion. 2010;50:1897-901.

163. Time (hr) Pentaglobin 6 mg/mL IgA Concentration Rate 0.5 10-7 0.4 ml/kg/hr 1.0 10-6 0.4 ml/kg/hr 1.5 10-5 0.4 ml/kg/hr 2.0 10-4 0.4 ml/kg/hr 2.5 10-3 0.4 ml/kg/hr 3.0 10-2 0.4ml/kg/hr 3.5 10-1 0.4ml/kg/hr 4.0 10-0 32 ml /hr (100 ml) Immunoglobulin A desensitization Protocol day 1

164. • Day 2 :Standard Plts IV infusion of 3 mL ->30 mL->300 mL • Day 3 :Standard FFP 3 units • Day 4 & 5 :Standard RBCs3 units with no adverse reactions • Day… :Weekly IV infusions of IgA-enriched immunoglobulins continue until after a successful liver transplantation Kiani-Alikhan S, Yong PF, Grosse-Kreul D, Height SE, Mijovic A, Suddle AR, et al. Successful desensitization to immunoglobulin A in a case of transfusion-related anaphylaxis. Transfusion. 2010;50:1897-901.

165. Indication for Screening anti IgA Autoantibody 1. Severe sIgAD 2. Partial sIgAD (and other pts) who have experienced an infusion reaction to a blood product

166. IgA deficiency with Associate disease 1. Recurrent infections :Prophylactic antibiotics 2. Allergic disorder : Standard treatment 3. Autoimmune condition : Standard treatment Yel L. Selective IgA deficiency. Journal of clinical immunology. 2010;30:10-6. Buckley RH,Orange JS. Primary Immunodeficiency Diseases In: Adkinson NF,Bochner BS, Burks AW, Busse WW,Holgate ST, Lemanske RF, O’Hehir RE, editors. Middleton’s allergy: principles & practice. 8 th ed. Philadelphia: Mosby-Elsevier; 2014. p.1144-74.

167. Vaccination and IgA deficiency Contraindicated Vaccines Risk-Specific Recommended Vaccines Effectiveness & Comments -OPV -BCG -Yellow fever -Other live vaccines appear to be safe. Pneumococcal All vaccines likely effective. Immune response might be attenuated. http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appenciec/A/immuno-table.pdf

168. Immunoglobulin Replacement Therapy •Recurrent infections &Poor quality of life •Fail aggressive ATB therapy & prophylaxis •Intolerable side effects or hypersensitivity to ATB Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. The Journal of allergy and clinical immunology. 2015.

169. Novel Therapy •Stimulation CD40/anti CD40 together with IL-4 & IL 10 •IL-21 Wang N, Hammarstrom L. IgA deficiency: what is new? Current opinion in allergy and clinical immunology. 2012;12(6):602-8.

170. Prognosis

171. Clinical heterogeneity and reversibility of selective immunoglobulin A deficiency in 80 children. Plebani A, Ugazio AG, Monafo V, Burgio GR. Clinical heterogeneity and reversibility of selective immunoglobulin A deficiency in 80 children. Lancet (London, England). 1986:829-31. 40 children with severe sIgAD 40 children with partial sIgAD Serum IgA level remain low 20 children Serum IgA level return normal 4 Years F/U

172. Aghamohammadi A, Mohammadi J, Parvaneh N, Rezaei N, Moin M, Espanol T, et al. Progression of selective IgA deficiency Time of Progression from Selective IgA Def to CVID from 7 months to 27 years

173. Take Home Message •IgA deficiency is the most common PID. •Decreased serum IgA level in the presence of normal level of other Ig isotype. •Most individuals with IgA deficiency are asymptomatic.

174. Take Home Message •Some patient may present with : Recurrent infections of the respiratory & gastrointestinal tracts : Allergic disorders : Autoimmune manifestations

175. Take Home Message •Asymptomatic pts :Education about the condition :Periodic monitoring

176. Take Home Message •Symptomatic patients :Prophylactic antibiotics :Vaccine (Pneumococcal vaccine) :Immunoglobulin :Standard tx Allergic and Autoimmune condition :Prevent anaphylactic reaction from blood transfusion

177. Thank You

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