selective immunoglobulin a deficiency

Selective Immunoglobulin A Deficiency

Yoavanit Srivaro M.D.

Outlines

•Introduction

•Immunoglobulin A and Its Functions

•Pathogenesis

•Epidemiology

•Clinical Manifestations

•Laboratory Evaluation

•Management

•Prognosis

Introduction

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.

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.

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 diagnosis: guidelines for clinicians at the bedside. Journal of clinical immunology. 2013;33:1078-87.

Serum Immunoglobulin Assay : IgG,IgA,IgM

IgG,IgA and/or IgM

B lymphocyte CD 19+

IgG,IgA and/or IgM

B lymphocyte CD 19+

CD 19+ absent

X-Linked Agammaglobulinemia

IgG,IgA and/or IgM

B lymphocyte CD 19+

CD 19+ absent

CD 19+ >1%

IgG,IgA and/or IgM

B lymphocyte CD 19+

CD 19+ absent

CD 19+ >1%

IgG and IgA and normal or IgM

IgG,IgA and/or IgM

B lymphocyte CD 19+

CD 19+ absent

CD 19+ >1%

Transient hypogammaglo-bulinemia of

infancy

IgG,IgA and/or IgM

B lymphocyte CD 19+

CD 19+ absent

CD 19+ >1%

infancy

IgG,IgA and/or IgM

B lymphocyte CD 19+

CD 19+ absent

CD 19+ >1%

infancy

HyperIgMsyndrome

IgG,IgA and/or IgMIgG and IgA and normal or IgM

Normal IgG,IgA,IgM

B lymphocyte CD 19+

CD 19+ absent CD 19+ >1%

CVIDHyperIgMsyndrome

infancy

Normal IgG,IgA,IgM

B lymphocyte CD 19+

infancy

Abn Specific Ab resonseto vaccine

Specific Ab def.

IgG,IgA and/or IgM

B lymphocyte CD 19+

CD 19+ absent

CD 19+ >1%

infancy

HyperIgMsyndrome

IgA Normal IgG,IgA,IgM

Specific Ab def.

B lymphocyte CD 19+

infancy

Specific Ab resonse to

vaccine

Specific Ab def.

B lymphocyte CD 19+

infancy

vaccine

Specific Ab def.

B lymphocyte CD 19+

infancy

vaccine

IgA with Specific Ab def.

Specific Ab def.

B lymphocyte CD 19+

infancy

vaccine

Selective IgA def.

IgA with Specific Ab def.

Specific Ab def.

Normal Low

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.

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.

Definition

been excluded

•Normal IgG antibody response to vaccinationBallas 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.

Definition

been excluded

Definition

been excluded

Definition

been excluded

Partial Ig A Deficiency

•Serum IgA at least 2 SD below normal for age

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.

Immunoglobulin A And Its Functions

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.

1953;10:193-4.

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.

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.

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.

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.

Figure 1. Human IgA structure.

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

Monomeric Serum IgA

Dimeric form IgA

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

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.

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.

FIGURE 14-7 A IgA class switching in the gut. T-dependent IgA class switching

FIGURE 14-7 B IgA class switching in the gut. T-independent IgA class switching

FIGURE 14-8 Transport of IgA across epithelial cells.

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.

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 .

Fig. 2 Simplified scheme of Fc alpha RI signaling pathways

Activation

Inhibition

Fig. 1 a Schematic representation of immunoglobulin A (IgA) binding to the Fc alpha RI–FcRc-chain

Fig. 1 b DC-SIGN/SIGNR1 and secretory IgA (SIgA) representation

Regulatory Function

Pathogenesis

Stem Cells Defect

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

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.

Block in differentiation of B cells to IgA antibody secreting plasma cell

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.

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.

Alpha heavy chain gene deletionsinvolving various segments on chromosome 14

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.

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.

TACI and BAFFR gene Abnormality

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.

Abnormality of The Cytokine network

Cunningham-Rundles C. Physiology of IgA and IgA deficiency. JClin Immunol. 2001;21:303–9.

• 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.

Genetic

MHC loci associations

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

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.

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.

Abnormalities in genes associated with autoimmunity

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.

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.

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.

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.

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.

IgG4 deficiency

Epidemiology

IgA deficiency is more common in Caucasians.

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

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.

Clinical Manifestations

Wide spectrum of clinical findings

• Asymtomatic

• Recurrent sinopulmonary infections

• Gastrointestinal infections and disorders

• Allergic disorder

• Autoimmune conditions

• 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.

Recurrent sinopulmonary infections

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.

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

Gastrointestinal infections and disorders

•Giardia lamblia

•Malabsorption

•Celiac disease

•Ulcerative colitis

•Nodular lymphoid hyperpalsia

•Giardia lamblia

•Malabsorption

•Celiac disease

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.

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.

•Giardia lamblia

•Malabsorption

•Celiac disease

•Giardia lamblia

•Malabsorption

•Celiac disease

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.

Allergic disorder

Autoimmune conditions

•This figure varies from 3.3 % to 33.6 %based on the age range of studied populations .

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.

•Genetic factor

Inhibition

Fig. 1 a Schematic representation of immunoglobulin A (IgA) binding to the Fc alpha RI–FcRc-chain

•Genetic factor

Autoimmune conditions

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.

Celiac Disease

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

Celiac Disease

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

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.

Malignancies

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.

Fig. 1 Malignancies in IgAD(IgA deficiency) patients andmatched general populationcomparators over 25 years offollow-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

Table 2 Malignancies and person-years :Conditional hazard ratio

Laboratory Evaluation

IgA deficiency should be a consideration in a patient with…?

•Recurrent respiratory infections

•Recurrent gastrointestinal infections

•Allergic disorders

•Autoimmune disorders

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.

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

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

Definition

been excluded

Management

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.

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

p.1144-74.

• 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

• 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.

Time(hr)

Pentaglobin6 mg/mL IgA

Concentration

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

• 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.

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

IgA deficiency with Associate disease

1. Recurrent infections :Prophylactic antibiotics

2. Allergic disorder : Standard treatment

3. Autoimmune condition : Standard treatment

p.1144-74.

Vaccination and IgA deficiency

Contraindicated Vaccines

Risk-SpecificRecommended Vaccines

Effectiveness & Comments

-OPV-BCG-Yellow fever-Other live vaccines appear to be safe.

Pneumococcal All vaccines likely effective. Immuneresponse might be attenuated.

http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appenciec/A/immuno-table.pdf

Immunoglobulin Replacement Therapy

•Recurrent infections &Poor quality of life

•Fail aggressive ATB therapy & prophylaxis

• Intolerable side effects or hypersensitivity to ATB

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.

Prognosis

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

Aghamohammadi A, Mohammadi J, Parvaneh N, Rezaei N, Moin M, Espanol T, et al. Progression of selective IgA deficiency to common variable immunodeficiency. International archives of allergy and immunology. 2008;147:87-92

Time of Progression from Selective IgA Def to CVID from 7 months to 27 years

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.

Take Home Message

•Some patient may present with

: Recurrent infections of the respiratory &

gastrointestinal tracts

: Allergic disorders

: Autoimmune manifestations

Take Home Message

•Asymptomatic pts

:Education about the condition

:Periodic monitoring

Take Home Message

•Symptomatic patients

:Prophylactic antibiotics

:Vaccine (Pneumococcal vaccine)

:Immunoglobulin

:Standard tx Allergic and Autoimmune condition

:Prevent anaphylactic reaction from blood transfusion

Thank You

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