B-Cell and T-Cell Combined Disorders

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The immune system’s lymphocyte component is divided into B cells and T cells. Traditionally, B cells have been believed to be the lymphocytes responsible for antibody production via maturation into plasma cells (ie, humoral immunity), and T cells have been believed to be the lymphocytes responsible for killing other cells or organisms (ie, cellular immunity). Currently, certain T lymphocytes (ie, T-helper cells) are known to be responsible for helping immature B cells develop into mature B cells. Other T lymphocytes (ie, T-suppressor/cytotoxic cells) possess the killing function and also inhibit B-cell development. Therefore, any T-cell disorder theoretically has the potential to cause defective B-cell function.

Because a major loss or dysfunction of T cells can cause secondary B-cell deficiency, numerous disorders have clinical manifestations of combined B-cell and T-cell deficiency, although the only pathology is in the T cell. In converse, some diseases appear to primarily involve the T cells and do not appear to affect antibody production. Those diseases are discussed in T-Cell Disorders.

Development of mature functioning B and T cells involves a complex series of steps, each of which may be defective, resulting in B-cell and T-cell deficiency. When T-cell deficiency is especially severe or involves the T-helper cell function, the deficiency causes an antibody deficiency. The most severe manifestations occur within the first 2 years of life as various types of severe combined immunodeficiency (SCID). See Omenn Syndrome and Purine Nucleoside Phosphorylase Deficiency for a discussion of other forms of SCID.

Omenn syndrome is the result of mutations in the genes coding for recombinases (recombination activating genes). RAG1 and RAG2 cause a defect in the variable diversity joining (VDJ) rearrangement needed for mature T and B cells to develop. Deficiency of purine nucleoside phosphorylase (PNP) and adenosine deaminase (ADA) elevates intracellular levels of deoxyguanosine and deoxyadenosine, respectively. [1] Deoxyguanosine and deoxyadenosine are more toxic in lymphocytes than in other cell types. Deficiency of the expression of major histocompatibility complex (MHC) class I and II cellular proteins also commonly manifests in early infancy with classic symptoms of SCID. Symptoms in affected patients indicate the crucial involvement of MHC proteins in the immune recognition of self and nonself.

In other B-cell and T-cell disorders, additional anomalies may predominate, and clinical manifestations suggestive of immunodeficiency may occur late in life. Recognize that patients with short-limbed skeletal dysplasia with cartilage-hair hypoplasia can also have either a T-cell or combined defect. See Cartilage-Hair Hypoplasia.

Male patients with thrombocytopenia and eczema may have Wiskott-Aldrich syndrome with defective T-cell function and resultant recurrent infections. They have poor antibody responses to polysaccharide antigens but elevated levels of serum immunoglobulin A (IgA) and immunoglobulin E (IgE) with low levels of immunoglobulin M (IgM). See Wiskott-Aldrich Syndrome.

Two autosomal recessive syndromes involving DNA repair indicate some interaction between the immune system and neurologic function. Ataxia-telangiectasia (AT) is a rare, autosomal recessive, neurodegenerative disorder in which the diagnosis is obvious when both ataxia and telangiectasia are present. Multisystemic manifestations of AT include motor impairments secondary to a neurodegenerative process, oculocutaneous telangiectasia, sinopulmonary infections, hypersensitivity to ionizing radiation, and a combined immunodeficiency that can be quite variable. This is discussed in additional detail in this article.

Nijmegen breakage syndrome (NBS) is also an autosomal recessive chromosomal instability syndrome. NBS is characterized by microcephaly with growth retardation, normal or impaired intelligence, birdlike facies, increased susceptibility to infection, humoral and cellular immunodeficiency, and high risk for lymphatic tumor development. Nearly all patients with NBS are homozygous for the same founder mutation, ie, deletion of 5 bp (657del5) in the NBS1 gene, which encodes the protein nibrin. Because most patients with NBS are of Slavonic origin, this frameshift mutation came to be called the Slavonic mutation.

These 2 syndromes, AT and NBS, are part of a family of mutations involving proteins involved in DNA repair. Ataxialike disorder (ATLD) syndrome involves a mutation in meiotic recombination 11 homolog (MRE11). These 3 syndromes are associated with decrease circulating levels of T cells (but circulating levels of B cells are normal) and often decreased levels of IgA, IgE, and IgG subclasses. Artemis deficiency (with mutations in the Artemis protein resulting in defective VDJ recombination) decreases both T cells and B cells and can be considered part of a subset of SCIDs. DNA ligase IV deficiency likewise results in circulating T cells and B cells and serum immunoglobulins. Finally, Bloom syndrome results from a mutation in the helicase enzyme called BLM RecQ. All of these defects in DNA repair are characterized by an increased risk of malignancy and radiation sensitivity.

Two syndromes indicate close interaction between the immune and endocrine systems: chronic mucocutaneous candidiasis (CMC) and immune dysregulation with polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. [2]

CMC is a complex disorder in which patients have persistent or recurrent infections of the skin, nails, and mucous membranes by Candida species. It can be broadly classified into familial (inherited) or nonfamilial (noninherited) forms. Familial forms are inherited as autosomal dominant or autosomal recessive and are associated with or without varying degrees of autoimmune endocrinopathy. Two other familial subtypes include an autosomal dominant form with nail candidiasis and intercellular adhesion molecule-1 (ICAM-1) deficiency and an autosomal recessive form with hyperimmunoglobulin E.

CMC is included as part of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disorder, which is also known as autoimmune polyglandular syndrome type I (APS I). [3] This disease has been mapped to chromosome 21q22.3 and the gene identified as the autoimmune regulator (AIRE) gene. It appears to be involved in DNA binding. At least 60 different disease-causing mutations in AIRE have been discovered and the role in various manifestations of CMC and APECED/APS I are under investigation.

IPEX syndrome is associated with mutations in the FOXP3 gene at Xp11.23. Affected males have diarrhea (enteropathy) and autoimmune phenomena primarily involving the endocrine system, such as diabetes or thyroid disease. Other autoimmune processes may include hemolytic anemia and collagen-vascular disease. The typical triad consists of enteropathy, dermatitis, and endocrine abnormalities. Most individuals with this condition do not live beyond age 3 years.

United States

Stiehm estimated that combined cellular and antibody deficiencies account for approximately 20% of primary immunodeficiencies. [4] AT is a rare disease with an estimated prevalence of less than 1 case per 100,000 population; the incidence of CMC is similar at 1 case per 103,000 population. Some report an increased frequency of approximately 1 case of AT per 40,000 births in the United States.

Newborn screening in California established the incidence of SCID as 1 case in 66,250 live births. According to the Centers for Disease Control and Prevention (CDC), only 16 states in the United States currently include SCID on newborn screening. Testing uses quantification of T-cell receptor excision circles (TRECs) to evaluate T-cell production by the thymus. TRECs are also used for evaluation of other T-cell immunodeficiency disorders, both acquired and congenital.[#IntroductionFrequencyInternational]

A study of data from a spectrum of 11 newborn screening programs determined that SCID, leaky SCID, and Omenn syndrome affected 1 in 58,000 infants. The survival rate was 92% for infants who received transplantation, enzyme replacement, and/or gene therapy. [5]

International

In Brazil, combined immunodeficiency defects accounted for 16 (9.6%) of 166 primary immunodeficiencies in children examined over 15 years. In Spain’s Registry for Primary Immunodeficiency Diseases, 14.7% were T-cell and combined deficiencies, similar to the 20.2% reported in the European registry report. In a survey of 201 Swedish patients from 1974-1979, 20.8% had combined T-cell and B-cell disorders.

The birth frequency of AT in the United Kingdom is approximately 1 case per 300,000 population. In the Slavonic population, the prevalence of AT appears higher (1:40,000-100,000) than the prevalence of NBS (1:60,000-120,000). CMC with APECED is inherited as an autosomal recessive trait and appears to be prevalent in genetically isolated populations of the Finns, the Iranian Jews, and the Sardinians (with prevalences of 1:25,000, 1:9000, and 1:14,500, respectively). Indeed, the Finnish series of patients is the largest internationally. [6]

Similar to patients with B-cell deficiency, a major cause of mortality and morbidity is recurrent upper and lower respiratory infections because patients cannot mount an adequate immune reaction. Patients’ increased susceptibility to development of malignancy also indicates the importance of T cells in immune surveillance and the role of cellular immunity in the protection against tumor cells. Abnormal immune systems in patients can produce autoimmune reactions in which an inappropriate exaggerated reaction can occur toward self-antigens.

Although combined B-cell and T-cell disorders are rare, they are described in all races.

No differences have been reported based on sex except in IPEX syndrome.

The disorders almost always occur in young infants, and the syndrome can often be recognized on the basis of its nonimmunologic manifestations.

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Hong M, Ryan KR, Arkwright PD, et al. Pattern recognition receptor expression is not impaired in patients with chronic mucocutanous candidiasis with or without autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. Clin Exp Immunol. 2009 Apr. 156(1):40-51. [Medline]. [Full Text].

Eyerich K, Foerster S, Rombold S, et al. Patients with chronic mucocutaneous candidiasis exhibit reduced production of Th17-associated cytokines IL-17 and IL-22. J Invest Dermatol. 2008 Nov. 128(11):2640-5. [Medline].

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Meloni A, Furcas M, Cetani F, et al. Autoantibodies against type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab. 2008 Nov. 93(11):4389-97. [Medline].

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Lee AY, Frith K, Schneider L, Ziegler JB. Haematopoietic stem cell transplantation for severe combined immunodeficiency: Long-term health outcomes and patient perspectives. J Paediatr Child Health. 2017 Aug. 53 (8):766-770. [Medline].

Pai SY, Logan BR, Griffith LM, Buckley RH, Parrott RE, Dvorak CC, et al. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med. 2014 Jul 31. 371(5):434-46. [Medline].

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Brand(Manufacturer)

Manufacturing Process

pH

Additives (IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors [eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs].)

Parenteral Form and Final Concentrations

IgA Content mcg/mL

Carimune NF

(ZLB Behring)

Kistler-Nitschmann fractionation, pH 4, nanofiltration

6.4-6.8

6% solution: 10% sucrose, < 20 mg NaCl/g protein

Lyophilized powder 3%, 6%, 9%, 12%

Trace

Flebogamma

(Grifols USA)

Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization

5.1-6

Sucrose free, contains 5% D-sorbitol

Liquid 5%

< 50

Gammagard Liquid 10%

(Baxter Bioscience)

Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation

4.6-5.1

0.25 M glycine

Ready-for-use liquid 10%

37

Gammar-P IV

(ZLB Behring)

Cohn-Oncley fraction II/III, ultrafiltration, pasteurization

6.4-7.2

5% solution: 5% sucrose, 3% albumin, 0.5% NaCl

Lyophilized powder 5%

< 20

Gamunex

(Talecris Biotherapeutics)

Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation

4-4.5

Contains no sugar, contains glycine

Liquid 10%

46

Gammaplex

(Bio Products)

Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation

4.8-5.1

Contains sorbitol (40 mg/mL); do not administer if fructose intolerant

Ready-for-use solution 5%

< 10

Iveegam EN

(Baxter Bioscience)

Cohn-Oncley fraction II/III, ultrafiltration, pasteurization

6.4-7.2

5% solution: 5% glucose, 0.3% NaCl

Lyophilized powder 5%

< 10

Polygam S/D

Gammagard S/D

(Baxter Bioscience for the American Red Cross)

Cohn-Oncley cold ethanol fractionation, followed by ultra centrafiltration and ion exchange chromatography, solvent detergent treated

6.4-7.2

5% solution: 0.3% albumin, 2.25% glycine, 2% glucose

Lyophilized powder 5%, 10%

< 1.6 (5% solution)

Octagam

(Octapharma USA)

9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events

Cohn-Oncley fraction II/III, ultrafiltration, low pH incubation, S/D treatment pasteurization

5.1-6

10% maltose

Liquid 5%

200

Panglobulin

(Swiss Red Cross for the American Red Cross)

Kistler-Nitschmann fractionation, pH 4, trace pepsin, nanofiltration

6.6

Per gram of IgG: 1.67 g sucrose, < 20 mg NaCl

Lyophilized powder 3%, 6%, 9%, 12%

720

Terry W Chin, MD, PhD Associate Clinical Professor, Department of Pediatrics, University of California, Irvine, School of Medicine; Associate Director, Cystic Fibrosis Center, Attending Staff Physician, Department of Pediatric Pulmonology, Allergy, and Immunology, Memorial Miller Children’s Hospital

Terry W Chin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American College of Chest Physicians, American Federation for Clinical Research, American Thoracic Society, California Society of Allergy, Asthma and Immunology, California Thoracic Society, Clinical Immunology Society, Los Angeles Pediatric Society, Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Noufa Alonazi, MD, MBBS Allergy and Immunology Postdoctoral Fellow, Department of Pediatrics, Loma Linda University and Medical Center

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Harumi Jyonouchi, MD Faculty, Division of Allergy/Immunology and Infectious Diseases, Department of Pediatrics, Saint Peter’s University Hospital

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Pediatric Research, Society for Mucosal Immunology

Disclosure: Nothing to disclose.

John Wilson Georgitis, MD Consulting Staff, Lafayette Allergy Services

John Wilson Georgitis, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Chest Physicians, American Lung Association, American Medical Writers Association, and American Thoracic Society

Disclosure: Nothing to disclose.

B-Cell and T-Cell Combined Disorders

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