Selective immunoglobulin A deficiency

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Selective immunoglobulin A deficiency
Immunglobulin A as Dimer.png
The dimeric IgA molecule. 1 H-chain, 2 L-chain, 3 J-chain, 4 secretory component
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Selective immunoglobulin A (IgA) deficiency (SIgAD [1] ) is a kind of immunodeficiency, a type of hypogammaglobulinemia. People with this deficiency lack immunoglobulin A (IgA), a type of antibody that protects against infections of the mucous membranes lining the mouth, airways, and digestive tract. It is defined as an undetectable serum IgA level in the presence of normal serum levels of IgG and IgM, in persons older than 4 years. It is the most common of the primary antibody deficiencies. Most such persons remain healthy throughout their lives and are never diagnosed.

Contents

Signs and symptoms

85–90% of IgA-deficient individuals are asymptomatic, although the reason for lack of symptoms is relatively unknown and continues to be a topic of interest and controversy. [2] Some patients with IgA deficiency have a tendency to develop recurrent sinopulmonary infections, gastrointestinal infections and disorders, allergies, autoimmune conditions, and malignancies. [2] These infections are generally mild and would not usually lead to an in-depth workup except when unusually frequent. They rarely present with severe reactions, including anaphylaxis, to blood transfusions or intravenous immunoglobulin due to the presence of IgA in these blood products. Patients have an increased susceptibility to pneumonia and recurrent episodes of other respiratory infections and a higher risk of developing autoimmune diseases in middle age. [3]

IgA deficiency and common variable immunodeficiency (CVID) feature similar B cell differentiation arrests, [4] but it does not present the same lymphocyte subpopulation abnormalities. [5] IgA-deficient patients may progress to panhypogammaglobulinemia characteristic of CVID. [4] Selective IgA and CVID are found in the same family. [4]

Cause

Selective IgA deficiency is inherited in less than half of cases, [6] but has been associated with differences in chromosomes 18, 14 and 6. Selective IgA deficiency is often inherited, but fewer than half of all cases but has been associated with some congenital intrauterine infections. [4]

Pathophysiology

Pathogenesis of IgA Deficiency

‘In IgA-deficient patients, the common finding is a maturation defect in B cells to produce IgA’. ‘In IgA deficiency, B cells express IgA; however, they are of immature phenotype with the coexpression of IgM and IgD, and they cannot fully develop into IgA-secreting plasma cells’. [7]

There is an inherited inability to produce immunoglobulin A (IgA), a part of the body's defenses against infection at the body's surfaces (mainly the surfaces of the respiratory and digestive systems). As a result, bacteria at these locations are somewhat more able to cause disease.[ citation needed ]

Types include:

Type OMIM GeneLocus
IGAD1 137100 Unknown; MSH5 suggested [8] [9] 6p21
IGAD2 609529 TNFRSF13B 17p11

Diagnosis

When suspected, the diagnosis can be confirmed by laboratory measurement of IgA level in the blood. SIgAD is an IgA level < 7 mg/dL with normal IgG and IgM levels (reference range 70–400 mg/dL for adults; children somewhat less). [10]

Treatment

The treatment consists of identification of co-morbid conditions, preventive measures to reduce the risk of infection, and prompt and effective treatment of infections. Infections in an IgA-deficient person are treated as usual (i.e., with antibiotics). There is no treatment for the underlying disorder. [11] All SIgAD patients, even if asymptomatic, should receive pneumococcal and influenza vaccines, but should avoid live attenuated vaccines. [12]

Use of IVIG as treatment

There is a historical popularity in using intravenous immunoglobulin (IVIG) to treat SIgAD, but the consensus is that there is no evidence that IVIG treats this condition. [13] [14] [15] In cases where a patient presents SIgAD and another condition which is treatable with IVIG, then a physician may treat the other condition with IVIG. [14] The use of IVIG to treat SIgAD without first demonstrating an impairment of specific antibody formation is not recommended. [14] [16] [17] [15] [13]

Prognosis

Prognosis is excellent, although there is an association with autoimmune disease. Of note, selective IgA deficiency can complicate the diagnosis of one such condition, celiac disease, as the deficiency masks the high levels of certain IgA antibodies usually seen in celiac disease. [18]

As opposed to the related condition CVID, selective IgA deficiency is not associated with an increased risk of cancer. [19]

Patients with Selective IgA deficiency rarely have severe reactions to blood transfusions. [20] Although Selective IgA deficiency is common, [21] [22] [23] severe reactions to blood transfusions are very rare. [20] [22] [24] People with selective IgA deficiency do not require special blood products unless they have a history of a severe allergic reaction to a blood transfusion. [25] [26] [27]

Epidemiology

Prevalence varies by population, but is on the order of 1 in 100 to 1 in 1000 people, [21] making it relatively common. SIgAD occurs in 1 in 39 to 1 in 57 people with celiac disease. This is much higher than the prevalence of selective IgA deficiency in the general population. [28] It is also significantly more common in those with type 1 diabetes.[ citation needed ]

It is more common in males than in females. [29]

See also

Related Research Articles

Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection and environmental factors, such as nutrition. Immunocompromisation may also be due to genetic diseases/flaws such as SCID.

<span class="mw-page-title-main">Wiskott–Aldrich syndrome</span> Medical condition

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia, immune deficiency, and bloody diarrhea. It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present with similar but less severe symptoms and are caused by mutations of the same gene.

<span class="mw-page-title-main">X-linked agammaglobulinemia</span> Medical condition

X-linked agammaglobulinemia (XLA) is a rare genetic disorder discovered in 1952 that affects the body's ability to fight infection. As the form of agammaglobulinemia that is X-linked, it is much more common in males. In people with XLA, the white blood cell formation process does not generate mature B cells, which manifests as a complete or near-complete lack of proteins called gamma globulins, including antibodies, in their bloodstream. B cells are part of the immune system and normally manufacture antibodies, which defend the body from infections by sustaining a humoral immunity response. Patients with untreated XLA are prone to develop serious and even fatal infections. A mutation occurs at the Bruton's tyrosine kinase (Btk) gene that leads to a severe block in B cell development and a reduced immunoglobulin production in the serum. Btk is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor BCR. Patients typically present in early childhood with recurrent infections, in particular with extracellular, encapsulated bacteria. XLA is deemed to have a relatively low incidence of disease, with an occurrence rate of approximately 1 in 200,000 live births and a frequency of about 1 in 100,000 male newborns. It has no ethnic predisposition. XLA is treated by infusion of human antibody. Treatment with pooled gamma globulin cannot restore a functional population of B cells, but it is sufficient to reduce the severity and number of infections due to the passive immunity granted by the exogenous antibodies.

Hypogammaglobulinemia is an immune system disorder in which not enough gamma globulins are produced in the blood. This results in a lower antibody count, which impairs the immune system, increasing risk of infection. Hypogammaglobulinemia may result from a variety of primary genetic immune system defects, such as common variable immunodeficiency, or it may be caused by secondary effects such as medication, blood cancer, or poor nutrition, or loss of gamma globulins in urine, as in nonselective glomerular proteinuria. Patients with hypogammaglobulinemia have reduced immune function; important considerations include avoiding use of live vaccines, and take precautionary measures when traveling to regions with endemic disease or poor sanitation such as receiving immunizations, taking antibiotics abroad, drinking only safe or boiled water, arranging appropriate medical cover in advance of travel, and ensuring continuation of any immunoglobulin infusions needed.

Common variable immunodeficiency (CVID) is an inborn immune disorder characterized by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM, and IgA. Symptoms generally include high susceptibility to pathogens, chronic lung disease, as well as inflammation and infection of the gastrointestinal tract.

<span class="mw-page-title-main">X-linked severe combined immunodeficiency</span> Medical condition

X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency disorder in which the body produces very few T cells and NK cells.

<span class="mw-page-title-main">Dysgammaglobulinemia</span> Type of immune disorder

Dysgammaglobulinemia is a type of immune disorder characterized by a reduction in some types of gamma globulins, resulting in heightened susceptibility to some infectious diseases where primary immunity is antibody based.

<span class="mw-page-title-main">Hyper IgM syndrome</span> Primary immune deficiency disorders

Hyper IgM syndrome is a rare primary immune deficiency disorders characterized by low or absent levels of serum IgG, IgA, IgE and normal or increased levels of serum IgM.

<span class="mw-page-title-main">Hyper-IgM syndrome type 5</span> Primary immune deficiency disorder

The fifth type of hyper-IgM syndrome has been characterized in three patients from France and Japan. The symptoms are similar to hyper IgM syndrome type 2, but the AICDA gene is intact.

Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a primary immunodeficiency (PID), the immune deficiency must be inborn, not caused by secondary factors such as other disease, drug treatment, or environmental exposure to toxins. Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. While there are over 430 recognized inborn errors of immunity (IEIs) as of 2019, the vast majority of which are PIDs, most are very rare. About 1 in 500 people in the United States are born with a primary immunodeficiency. Immune deficiencies can result in persistent or recurring infections, auto-inflammatory disorders, tumors, and disorders of various organs. There are currently limited treatments available for these conditions; most are specific to a particular type of PID. Research is currently evaluating the use of stem cell transplants (HSCT) and experimental gene therapies as avenues for treatment in limited subsets of PIDs.

An immune disorder is a dysfunction of the immune system. These disorders can be characterized in several different ways:

<span class="mw-page-title-main">IgG deficiency</span> Form of immune disorder

IgG deficiency is a form of dysgammaglobulinemia where the proportional levels of the IgG isotype are reduced relative to other immunoglobulin isotypes.

Transient hypogammaglobulinemia of infancy is a form of hypogammaglobulinemia appearing after birth, leading to a reduction in the level of IgG, and also sometimes IgA and IgM.

<span class="mw-page-title-main">Isolated primary immunoglobulin M deficiency</span> Medical condition

Isolated primary immunoglobulin M deficiency is a poorly defined dysgammaglobulinemia characterized by decreased levels of IgM while levels of other immunoglobulins are normal. The immunodeficiency has been associated with some clinical disorders including recurrent infections, atopy, Bloom's syndrome, celiac disease, systemic lupus erythematosus and malignancy, but, surprisingly, SIgMD seems to also occur in asymptomatic individuals. High incidences of recurrent upper respiratory tract infections (77%), asthma (47%) and allergic rhinitis (36%) have also been reported. SIgMD seems to be a particularly rare antibody deficiency with a reported prevalence between 0.03% and 0.1%.

<span class="mw-page-title-main">Humoral immune deficiency</span> Medical condition

Humoral immune deficiencies are conditions which cause impairment of humoral immunity, which can lead to immunodeficiency. It can be mediated by insufficient number or function of B cells, the plasma cells they differentiate into, or the antibody secreted by the plasma cells. The most common such immunodeficiency is inherited selective IgA deficiency, occurring between 1 in 100 and 1 in 1000 persons, depending on population. They are associated with increased vulnerability to infection, but can be difficult to detect in the absence of infection.

Thymoma with immunodeficiency is a rare disorder that occurs in adults in whom hypogammaglobulinemia, deficient cell-mediated immunity, and thymoma may develop almost simultaneously. Most reported cases are in Europe, though it occurs globally.

Immunoglobulin therapy is the use of a mixture of antibodies to treat several health conditions. These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory demyelinating polyneuropathy, Kawasaki disease, certain cases of HIV/AIDS and measles, Guillain–Barré syndrome, and certain other infections when a more specific immunoglobulin is not available. Depending on the formulation it can be given by injection into muscle, a vein, or under the skin. The effects last a few weeks.

Granulomatous–lymphocytic interstitial lung disease (GLILD) is a lung complication of common variable immunodeficiency disorders (CVID). It is seen in approximately 15% of patients with CVID. It has been defined histologically as the presence of (non-caseating) granuloma and lymphoproliferation in the lung. However, as GLILD is often associated with other auto-immune features such as splenomegaly, adenopathy and cytopenias, a definition based on abnormalities on lung imaging together with evidence of granulomatous inflammation elsewhere has also been employed.

Suranjith Seneviratne is a doctor from Sri Lanka who practices in allergology and immunology.

References

  1. ↑ Hammarström L, Vorechovsky I, Webster D (May 2000). "Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID)". Clinical and Experimental Immunology . 120 (2): 225–231. doi:10.1046/j.1365-2249.2000.01131.x. PMC   1905641 . PMID   10792368.
  2. 1 2 Yel, L. (2010) 'Selective IgA Deficiency', Journal of Clinical Immunology, 30(1), pp. 10-16.
  3. ↑ Koskinen S (1996). "Long-term follow-up of health in blood donors with primary selective IgA deficiency". J Clin Immunol. 16 (3): 165–70. doi:10.1007/BF01540915. PMID   8734360. S2CID   28529140.
  4. 1 2 3 4 Harrison's Principles of Internal Medicine, 17th edition, pag. 2058
  5. ↑ Litzman J, Vlková M, Pikulová Z, Stikarovská D, Lokaj J (February 2007). "T and B lymphocyte subpopulations and activation/differentiation markers in patients with selective IgA deficiency". Clin. Exp. Immunol. 147 (2): 249–54. doi:10.1111/j.1365-2249.2006.03274.x. PMC   1810464 . PMID   17223965.
  6. ↑ Cunningham-Rundles C. (1990). "Genetic Aspects of IgA Deficiency". Adv Hum. Genet. 19: 235–266. doi:10.1007/978-1-4757-9065-8_4. PMID   2193490.
  7. ↑ Yel, L. (2010). "Selective IgA Deficiency". J Clin Immunol. 30 (1): 10–16. doi:10.1007/s10875-009-9357-x. PMC   2821513 . PMID   20101521.
  8. ↑ Sekine H, Ferreira RC, Pan-Hammarström Q, et al. (April 2007). "Role for Msh5 in the regulation of Ig class switch recombination". Proc. Natl. Acad. Sci. U.S.A. 104 (17): 7193–8. Bibcode:2007PNAS..104.7193S. doi: 10.1073/pnas.0700815104 . PMC   1855370 . PMID   17409188.
  9. ↑ Online Mendelian Inheritance in Man (OMIM): 137100
  10. ↑ Swain S, Selmi C, Gershwin ME, Teuber SS (December 2019). "The clinical implications of selective IgA deficiency". Journal of Translational Autoimmunity. 2: 100025. doi:10.1016/j.jtauto.2019.100025. ISSN   2589-9090. PMC   7388344 . PMID   32743511.
  11. ↑ Vosughimotlagh A, Rasouli SE, Rafiemanesh H, Safarirad M, Sharifinejad N, Madanipour A, Dos Santos Vilela MM, Heropolitańska-Pliszka E, Azizi G (2023-08-28). "Clinical manifestation for immunoglobulin A deficiency: a systematic review and meta-analysis". Allergy, Asthma & Clinical Immunology. 19 (1): 75. doi: 10.1186/s13223-023-00826-y . ISSN   1710-1492. PMC   10463351 . PMID   37641141.
  12. ↑ Swain S, Selmi C, Gershwin ME, Teuber SS (December 2012). "The clinical implications of selective IgA deficiency". Journal of Translational Autoimmunity. 2: 100025. doi:10.1016/j.jtauto.2019.100025. ISSN   2589-9090. PMC   7388344 . PMID   32743511.
  13. 1 2 American Academy of Allergy, Asthma, and Immunology. "Five Things Physicians and Patients Should Question" (PDF). Choosing Wisely: An Initiative of the ABIM Foundation. American Academy of Allergy, Asthma, and Immunology . Retrieved August 14, 2012.
  14. 1 2 3 Francisco A. Bonilla, I. Leonard Bernstein, David A. Khan, Zuhair K. Ballas, Javier Chinen, Michael M. Frank, Lisa J. Kobrynski, Arnold I. Levinson, Bruce Mazer (May 2005). "Practice parameter for the diagnosis and management of primary immunodeficiency" (PDF). Annals of Allergy, Asthma & Immunology. 94 (5): S1–S63. doi:10.1016/s1081-1206(10)61142-8. PMID   15945566. Archived from the original (PDF) on 11 November 2011. Retrieved 27 August 2012.
  15. 1 2 Perez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, El-Gamal Y, Harville TO, Hossny E (2017). "Update on the use of immunoglobulin in human disease: A review of evidence". Journal of Allergy and Clinical Immunology. 139 (3): S1–S46. doi: 10.1016/j.jaci.2016.09.023 . PMID   28041678.
  16. ↑ Hammarström L, Vorechovsky I, Webster D (2000). "Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID)". Clinical and Experimental Immunology. 120 (2): 225–231. doi:10.1046/j.1365-2249.2000.01131.x. PMC   1905641 . PMID   10792368.
  17. ↑ Mark Ballow (2008). "85". In Robert R. Rich (ed.). Clinical immunology : principles and practice (3rd ed.). St. Louis, Mo.: Mosby/Elsevier. pp. 1265–1280. ISBN   978-0323044042.
  18. ↑ Prince HE, Gary L. Norman, Walter L. Binder (November 2002). "Validation of an In-House Assay for Cytomegalovirus Immunoglobulin G (CMV IgG) Avidity and Relationship of Avidity to CMV IgM Levels". Clin Vaccine Immunol. 9 (6): 1295–1300. doi:10.1128/CDLI.9.4.824-827.2002. PMC   120015 . PMID   12093680.
  19. ↑ Mellemkjaer L, Hammarstrom L, Andersen V, et al. (2002). "Cancer risk among patients with IgA deficiency or common variable immunodeficiency and their relatives: a combined Danish and Swedish study". Clin. Exp. Immunol. 130 (3): 495–500. doi:10.1046/j.1365-2249.2002.02004.x. PMC   1906562 . PMID   12452841.
  20. 1 2 Vassallo RR (2020). "Review: IgA anaphylactic transfusion reactions. Part I. Laboratory diagnosis, incidence, and supply of IgA-deficient products". Immunohematology. 20 (4): 226–233. doi: 10.21307/immunohematology-2019-454 . ISSN   0894-203X. PMID   15679454.
  21. 1 2 "IgA Deficiency: Immunodeficiency Disorders: Merck Manual Professional" . Retrieved 2008-03-01.
  22. 1 2 Tacquard C, Boudjedir K, Carlier M, Muller JY, Gomis P, Mertes PM (2017). "Hypersensitivity transfusion reactions due to IgA deficiency are rare according to French hemovigilance data". Journal of Allergy and Clinical Immunology. 140 (3): 884–885. doi: 10.1016/j.jaci.2017.03.029 . PMID   28414063.
  23. ↑ Yazdani R, Azizi G, Abolhassani H, Aghamohammadi A (2017). "Selective IgA Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management". Scandinavian Journal of Immunology. 85 (1): 3–12. doi: 10.1111/sji.12499 . PMID   27763681.
  24. ↑ "SHOT Report, Summary and Supplement 2017". Serious Hazards of Transfusion. Retrieved 2019-04-26.
  25. ↑ "5.2 Non-infectious hazards of transfusion". Handbook of transfusion medicine. Norfolk, Derek (5th ed.). London: Stationery Office. 2013. ISBN   9780117068469. OCLC   869523772.{{cite book}}: CS1 maint: others (link)
  26. ↑ Tinegate H, Birchall J, Gray A, Haggas R, Massey E, Norfolk D, Pinchon D, Sewell C, Wells A (2012). "Guideline on the investigation and management of acute transfusion reactions Prepared by the BCSH Blood Transfusion Task Force". British Journal of Haematology. 159 (2): 143–153. doi: 10.1111/bjh.12017 . PMID   22928769. S2CID   9150295.
  27. ↑ "IgA deficient components". transfusion.com.au. Retrieved 2019-04-26.
  28. ↑ McGowan KE, Lyon EM, Butzner JD (July 2008). "Celiac Disease and IgA Deficiency: Complications of Serological Testing Approaches Encountered in the Clinic". Clinical Chemistry. 54 (7): 1203–1209. doi: 10.1373/clinchem.2008.103606 . PMID   18487281.
  29. ↑ Weber-Mzell D, Kotanko P, Hauer AC, et al. (March 2004). "Gender, age and seasonal effects on IgA deficiency: a study of 7293 Caucasians". Eur. J. Clin. Invest. 34 (3): 224–8. doi:10.1111/j.1365-2362.2004.01311.x. PMID   15025682. S2CID   25545688.
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