Antibody Deficiency Disorder

Article Author:
Angel Justiz Vaillant
Article Editor:
Kamleshun Ramphul
Updated:
2/22/2019 4:06:46 PM
PubMed Link:
Antibody Deficiency Disorder

Introduction

Antibodies or immunoglobulins (Ig) play an important role in the immune system mechanisms of defense. They fight off extracellular pathogens, for instance, bacteria and can neutralize viruses when they are in the bloodstream and other body fluids. Normal individuals have 5 classes of immunoglobulins, which are IgM, IgG, IgA, IgD and IgE and immunoglobulin subclasses including IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.[1] Sometimes an antibody deficiency disorder takes place. It can happen due to several causes including a genetic absence of an important enzyme in B-cell development that renders immature B cells that are unable to proliferate into mature Ig-producing B cells or may be caused when T lymphocytes do not signal B lymphocytes or are idiopathic.[2][3] 

The most common antibody deficiency disorders[4] include:

  • X-linked agammaglobulinemia (Bruton disease)[5][6]
  • Transient hypogammaglobulinemia of newborn
  • Selective Ig immunodeficiencies, for example, IgA selective deficiency
  • Super IgM syndrome
  • Common variable immunodeficiency disorder[7]

Etiology

X-linked Agammaglobulinemia (Bruton Disease)

It is seen in boys. It is due to a failure of pre B cells to differentiate into mature B lymphocytes as caused by a mutation in the gene that encodes for a tyrosine kinase protein needed for further differentiation.[4][8]

Transient Hypogammaglobulinemia of Newborn

It is a physiological reaction of the body after the maternal antibody disappearance about 4 to 6 months of age. The child is susceptible to recurrent infections similar to those seen in X-linked agammaglobulinemia. Once the child's immune system matures and makes antibody, this problem is corrected.[9]

Selective Ig Immunodeficiencies (IgA selective deficiency)

Normally, antibodies switch from IgM to other classes including IgG and IgA. Sometimes there is malfunctioning in heavy-chain gene switching and causes this problem.[10]

Super IgM Syndrome

In this disease the gene encoding the CD40 ligand on T cells is anomalous. That creates that B and T-lymphocyte cooperation in the immune response be compromised. The failure to interact with CD40 results in an inability of the B cell to switch from the production of IgM to the other classes of antibodies.[6][11]

Common Variable Immunodeficiency Disorder

It expresses in the second or third decade of life or later. It has an unknown etiology.[12]

Epidemiology

Data have shown that the most prevalent immunodeficiency disorders are the antibody deficiencies. These have been documented in many countries. For instance, in Singapore, 39 patients were diagnosed with immunodeficiency between 1990 and 2000 and the 41% were antibody deficiency.[13] Similarly, in South Africa (51%), [14], Korea (53.3%)[15] and Taiwan (46%)[16]reported this problem. In Denmark, medical records were reviewed and identified a CVID prevalence of 1:26,000, a peak in the fourth decade and the frequency of respiratory infections was 98%. Other problems such as bronchiectasis (36%) and splenomegaly (22.4%) were reported.[7]

Pathophysiology

Antibodies or immunoglobulins protect against extracellular microorganisms such as bacteria. They are produced by plasma cells, which are the product of the differentiation of mature B lymphocytes. Antibody deficiencies may occur due to lack of B-cells maturation, missing enzymes or failure of T-cell stimulatory signals for appropriate antibody production. In transient hypogammaglobulinemia of infancy, recurrent bacterial infections occur in children until their immune system matures.[17][6]

Histopathology

X-linked agammaglobulinemia lacks germinal centers, and lymphoid architecture is grossly altered. Hyper-IgM syndrome results in elevated IgM concentrations along with IgG and IgA-selective immunodeficiency.[18] The gallbladder in these patients shows alterations in submucosa that consists of cells with eccentric nuclei and pink-staining cytoplasm. These cells produce large quantities of IgM. Several immunodeficiencies can manifest lymph nodes with multiple B-cell follicles of variable sizes and proliferation centers when immunohistochemical staining for CD21 and CD79a is used.

History and Physical

In antibody immunodeficiency disorders, there is a history of:

  • Recurrent bacterial infections
  • Fever
  • Opportunistic infections
  • Frequent use of antimicrobials without noticeable improvement[6][19]

 The physical findings[18][20][21][22][23][24][25] include:

  • Bacteremia
  • Sinus pulmonary infections (e.g., pneumonia)
  • Otitis media
  • Meningitis
  • Septicemia
  • Arthritis
  • A cough
  • Malaise
  • Intestinal malabsorption
  • Bronchiectasis
  • Recurrent tonsillitis
  • A sore throat
  • Purulent conjunctivitis
  • Pyodermitis
  • Failure to thrive 
  • Diarrhea    
  • Low set ears and facial dysmorphisms  
  • Recurrent abscess  
  • Septic shock    
  • Asthenia  
  • Anorexia   
  • Loss of weight 
  • Aphthous stomatitis
  • Urinary sepsis
  • Denture abnormalities and periodontitis
  • Lymphoproliferative disease
  • Sinus pulmonary infections
  • Viral infections

Evaluation

The immunological investigation of a patient with antibody deficiency includes the assessment of both B and T lymphocytes and other investigations[6][20][26][27] as follow: 

Quantitative Serum Immunoglobulins

  • IgG
  • IgM
  • IgA

IgG Sub-Classes

  • IgG1
  • IgG2
  • IgG3
  • IgG4

B-cell Quantitative Assessment

  • Levels of CD19
  • Levels of CD20
  • Levels of CD21
  • Levels of CD81
  • Levels of CD 225

Antibody Activity

Detection of isohemagglutinins (IgM)

  • Anti-type A blood
  • Anti-type B blood

IgG antibodies (post-exposure)

  • Rubella
  • Measles
  • Varicella Zoster

IgG antibodies (post-immunization)

  • Tetanus toxoid
  • Diphtheria toxoid
  • Pneumococcal polysaccharide
  • Polio

Other assays

  • Serum protein electrophoresis

Blood Lymphocyte T Subpopulations

  • Total lymphocyte count
  • T lymphocytes (CD3, CD4, and CD8)
  • CD4/CD8 ratio

Lymphocyte Stimulation Assays

  • Phorbol ester and ionophore
  • Phytohemagglutinin
  • Antiserum to CD3

Phagocytic Function 

Nitroblue tetrazolium (NBT) test (before and after stimulation with endotoxin)

  • Unstimulated
  • Stimulated

Neutrophil mobility

  • In medium alone
  • In the presence of chemoattractant

Microbiological Studies

  • Stool (testing for bacterial infection)
  • Sputum (bacterial culture)
  • Cerebrospinal fluid (culture, chemistry, and histopathology)
  • Blood culture

Levels of Cytokines

  • IL-1
  • IL-2
  • IL-4
  • IL-5
  • IL-6
  • IL-13
  • IL-17
  • IL-22

Other Investigations 

  • Complete blood cell count   
  • Blood chemistry
  • Chest x-ray
  • Diagnostic ultrasound
  • CT scan
  • Fluorescent in situ hybridization (FISH)
  • DNA testing 

Treatment / Management

Antibody deficiency after diagnosis can be received intravenous immunoglobulin (IVIG) replacement therapy that is mostly IgG, but it may be enriched with IgM and IgA.[28] It can be applied intravenously or intra-subcutaneously. Other medications used include antimicrobials such as broad-spectrum antibiotics and metronidazole, which may be used if anaerobes bacteria are suspected. Transfer factor is used if an underlying T-cell failure is suspected.[6][22]

Bone marrow transplantation (BMT) and gene therapy, which remain experimental, can be the solution for those deficiencies caused by genetic abnormalities, for instance, the use of BMT in X-linked agammaglobulinemia.[29][30][31] In case of septic shock treatment with steroids is reserved. Nutritional supplements can be administered including vitamins A, C, E and B6, iron, zinc, selenium, and copper.[32]

Differential Diagnosis

The most important differential diagnosis includes the following: X-linked agammaglobulinemia characterizes by recurrent bacterial infections in boys, and genetic studies may reveal the presence of Bruton's tyrosine kinase (BTK) mutations. Transient hypogammaglobulinemia of newborn presents in newborns above the age of 4 months, and characterizes by recurrent pneumonia, meningitis, otitis media and other problems that resemble Bruton's disease. It is a physiological defect in the immune system caused by maternal IgG disappearance and corrected soon but requires treatment. In super-IgM syndrome, recurrent bacterial infections occur, but the cause of this illness is a mutation in the gene encoding for CD40 on T lymphocytes that causes a failure in T and B lymphocyte cooperation. Common variable immunodeficiency presents with recurrent bacterial infections including sinopulmonary problems but later in life (second-fourth decade), and the diagnosis is made once all causes of immunodeficiency have been ruled out.[6][7][21][33]

Antibody deficiency may present in other diseases including:

  • Multiple myelomas
  • Burns
  • Severely combined immunodeficiency disorders (SCID)
  • Immunodeficiency with ataxia-telangiectasia
  • DiGeorge syndrome
  • Lymphomas
  • Acute leukemia and others lymphoproliferative disorders 
  • Malnutrition
  • Interleukin-12 receptor deficiency
  • HIV/AIDS
  • Use of immunosuppressors
  • Systemic lupus erythematosus
  • Bare leukocyte syndrome
  • Organ transplantation recipient
  • Sarcoidosis
  • Amyloidosis
  • Interferon-gamma (IFN-gamma) receptor deficiency
  • Chronic granulomatous disease
  • Wiskott-Aldrich syndrome
  • Obesity
  • Chronic renal failure
  • C3 deficiency
  • Toll-like receptor deficiency and other innate immune system-related deficiencies
  • X-linked lymphoproliferative (XLP) syndrome
  • Zinc deficiency
  • TRAF3 adaptor molecule deficiency
  • WHIM syndrome
  • UNC93B deficiency
  • Down syndrome
  • Hemoglobinopathy

Prognosis

Antibody deficiency disorders have a better prognosis if the can be treated with intravenous immunoglobulins (IVIG) or subcutaneous infusions once a week. The use of broad-spectrum antibiotics can improve life expectancy. X-linked agammaglobulinemia has a poor prognosis that can improve if bone marrow transplantation if successfully practiced. Transient hypogammaglobulinemia of infancy has the best prognosis because it is due to an immaturity of the neonate's immune system and is correct once their immunoglobulin synthesis starts.

Pearls and Other Issues

  • Immune deficiency may be primary or secondary
  • Primary occurs when certain cells or a part of the immune system does not work properly due to a genetic defect of the immune system
  • Secondary occurs when the immune system works properly but the function is compromised due to external factors (e.g. viral infections, treatment with immunosuppressors and malnutrition).

References

[1] Justiz Vaillant AA,Ramphul K, Immunoglobulin 2018 Jan;     [PubMed PMID: 30035936]
[2] Prevalence of Hypogammaglobulinemia in Adult Invasive Pneumococcal Disease., Cowan J,Do TL,Desjardins S,Ramotar K,Corrales-Medina V,Cameron DW,, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2018 Feb 1     [PubMed PMID: 29401274]
[3] Gernez Y,Baker MG,Maglione PJ, Humoral immunodeficiencies: conferred risk of infections and benefits of immunoglobulin replacement therapy. Transfusion. 2018 Dec;     [PubMed PMID: 30536429]
[4] Primary immunodeficiencies: 2009 update., Notarangelo LD,Fischer A,Geha RS,Casanova JL,Chapel H,Conley ME,Cunningham-Rundles C,Etzioni A,Hammartröm L,Nonoyama S,Ochs HD,Puck J,Roifman C,Seger R,Wedgwood J,, The Journal of allergy and clinical immunology, 2009 Dec     [PubMed PMID: 20004777]
[5] Filion CA,Taylor-Black S,Maglione PJ,Radigan L,Cunningham-Rundles C, Differentiation of Common Variable Immunodeficiency From IgG Deficiency. The journal of allergy and clinical immunology. In practice. 2018 Dec 14;     [PubMed PMID: 30557717]
[6] Immunodeficiency, Justiz Vaillant AA,Qurie A,,, 2018 Jan     [PubMed PMID: 29763203]
[7] Identification and Characterization of a Nationwide Danish Adult Common Variable Immunodeficiency Cohort., Westh L,Mogensen TH,Dalgaard LS,Bernth Jensen JM,Katzenstein T,Hansen AE,Larsen OD,Terpling S,Nielsen TL,Larsen CS,, Scandinavian journal of immunology, 2017 Jun     [PubMed PMID: 28370285]
[8] Geha RS, Antibody deficiency syndromes and novel immunodeficiencies. The Pediatric infectious disease journal. 1988 May;     [PubMed PMID: 3041359]
[9] Moise A,Nedelcu FD,Toader MA,Sora SM,Tica A,Ferastraoaru DE,Constantinescu I, Primary immunodeficiencies of the B lymphocyte. Journal of medicine and life. 2010 Jan-Mar;     [PubMed PMID: 20302197]
[10] Moschese V,Chini L,Graziani S,Sgrulletti M,Gallo V,Di Matteo G,Ferrari S,Di Cesare S,Cirillo E,Pession A,Pignata C,Specchia F, Follow-up and outcome of symptomatic partial or absolute IgA deficiency in children. European journal of pediatrics. 2019 Jan;     [PubMed PMID: 30269248]
[11] Evaluation of infectious and non-infectious complications in patients with primary immunodeficiency., Bazregari S,Azizi G,Tavakol M,Asgardoon MH,Kiaee F,Tavakolinia N,Valizadeh A,Abolhassani H,Aghamohammadi A,, Central-European journal of immunology, 2017     [PubMed PMID: 29479289]
[12] [Common variable immune deficiency in adults: focus on pulmonary complications]., Fomina DS,Bobrikova EN,Sinyavkin DO,Parshin VV,, Terapevticheskii arkhiv, 2017     [PubMed PMID: 29488483]
[13] Lim DL,Thong BY,Ho SY,Shek LP,Lou J,Leong KP,Chng HH,Lee BW, Primary immunodeficiency diseases in Singapore--the last 11 years. Singapore medical journal. 2003 Nov     [PubMed PMID: 15007498]
[14] Naidoo R,Ungerer L,Cooper M,Pienaar S,Eley BS, Primary immunodeficiencies: a 27-year review at a tertiary paediatric hospital in Cape Town, South Africa. Journal of clinical immunology. 2011 Feb     [PubMed PMID: 20859665]
[15] Rhim JW,Kim KH,Kim DS,Kim BS,Kim JS,Kim CH,Kim HM,Park HJ,Pai KS,Son BK,Shin KS,Oh MY,Woo YJ,Yoo Y,Lee KS,Lee KY,Lee CG,Lee JS,Chung EH,Choi EH,Hahn YS,Park HY,Kim JG, Prevalence of primary immunodeficiency in Korea. Journal of Korean medical science. 2012 Jul     [PubMed PMID: 22787376]
[16] Lee WI,Kuo ML,Huang JL,Lin SJ,Wu CJ, Distribution and clinical aspects of primary immunodeficiencies in a Taiwan pediatric tertiary hospital during a 20-year period. Journal of clinical immunology. 2005 Mar     [PubMed PMID: 15821893]
[17] Justiz Vaillant AA,Qurie A, Interleukin . 2018 Jan     [PubMed PMID: 29763015]
[18] Ferastraoaru D,Gross R,Rosenstreich D, Increased malignancy incidence in IgE deficient patients not due to concomitant Common Variable Immunodeficiency. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2017 Sep     [PubMed PMID: 28778662]
[19] Justiz Vaillant AA,Zito PM, Neutropenia . 2018 Jan     [PubMed PMID: 29939524]
[20] Hoeger B,Serwas NK,Boztug K, Human NF-κB1 Haploinsufficiency and Epstein-Barr Virus-Induced Disease-Molecular Mechanisms and Consequences. Frontiers in immunology. 2017     [PubMed PMID: 29403474]
[21] Azizi G,Tavakol M,Rafiemanesh H,Kiaee F,Yazdani R,Heydari A,Abouhamzeh K,Anvari P,Mohammadikhajehdehi S,Sharifia L,Bagheri Y,Mohammadi H,Abolhassani H,Aghamohammadi A, Autoimmunity in a cohort of 471 patients with primary antibody deficiencies. Expert review of clinical immunology. 2017 Nov     [PubMed PMID: 29019451]
[22] Berger M,Geng B,Cameron DW,Murphy LM,Schulman ES, Primary immune deficiency diseases as unrecognized causes of chronic respiratory disease. Respiratory medicine. 2017 Nov     [PubMed PMID: 29229095]
[23] Yousefzadegan S,Tavakol M,Abolhassani H,Nadjafi A,Mansouri S,Yazdani R,Azizi G,Negahdari B,Rezaei N,Aghamohammadi A, Systematic investigation for underlying causes of recurrent infections in children: surveillance of primary immunodeficiency. European annals of allergy and clinical immunology. 2018 Mar     [PubMed PMID: 29384110]
[24] Gompels MM,Hodges E,Lock RJ,Angus B,White H,Larkin A,Chapel HM,Spickett GP,Misbah SA,Smith JL, Lymphoproliferative disease in antibody deficiency: a multi-centre study. Clinical and experimental immunology. 2003 Nov     [PubMed PMID: 14616793]
[25] Dropulic LK,Cohen JI, Severe viral infections and primary immunodeficiencies. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2011 Nov     [PubMed PMID: 21960712]
[26] Taneja A,Chhabra A, Bruton Agammaglobulinemia . 2018 Jan     [PubMed PMID: 28846295]
[27] de la Morena MT, Clinical Phenotypes of Hyper-IgM Syndromes. The journal of allergy and clinical immunology. In practice. 2016 Nov - Dec     [PubMed PMID: 27836054]
[28] Dhandha MM,Siegfried EC,Knutsen AP, Treatment of selective antibody deficiency with IVIG resulting in decreased frequency of streptococcal infection and improvement of guttate psoriasis. Dermatology online journal. 2017 Aug 15     [PubMed PMID: 29469743]
[29] Abu-Arja RF,Chernin LR,Abusin G,Auletta J,Cabral L,Egler R,Ochs HD,Torgerson TR,Lopez-Guisa J,Hostoffer RW,Tcheurekdjian H,Cooke KR, Successful hematopoietic cell transplantation in a patient with X-linked agammaglobulinemia and acute myeloid leukemia. Pediatric blood & cancer. 2015 Sep     [PubMed PMID: 25900577]
[30] Verma N,Thaventhiran A,Gathmann B,Thaventhiran J,Grimbacher B, Therapeutic management of primary immunodeficiency in older patients. Drugs & aging. 2013 Jul     [PubMed PMID: 23605785]
[31] Azizi G,Kiaee F,Yaslianifard S,Rafiemanesh H,Mohammadikhajehdehi S,Mohammadi H,Miresmaeeli SS,Pour LH,Poor Heravi SA,Sharifi L,Yazdani R,Abolhassani H,Aghamohammadi A, Mannose-Binding Lectin Protein Deficiency Among Patients with Primary Immunodeficiency Disease Receiving IVIG Therapy. Endocrine, metabolic & immune disorders drug targets. 2018 Feb 13     [PubMed PMID: 29119939]
[32] Agarwal S,Mayer L, Diagnosis and treatment of gastrointestinal disorders in patients with primary immunodeficiency. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2013 Sep     [PubMed PMID: 23501398]
[33] Qiu KY,Liao XY,Wu RH,Huang K,Fang JP,Zhou DH, X-linked Hyper-IgM Syndrome: A Phenotype of Crohn's Disease with Hemophagocytic Lymphohistiocytosis. Pediatric hematology and oncology. 2017 Nov     [PubMed PMID: 29303623]