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Primary humoral immunodeficiencies: An overview

Primary humoral immunodeficiencies: An overview
Author:
Ivan K Chinn, MD
Section Editor:
Jordan S Orange, MD, PhD
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Nov 2022. | This topic last updated: Jun 22, 2021.

INTRODUCTION — Primary immunodeficiency diseases encompass over 400 intrinsic defects of immunity, most of which are inheritable [1,2]. These conditions are classified into 10 main groups, including immunodeficiencies affecting cellular and humoral immunity; combined immunodeficiencies with associated or syndromic features; predominantly antibody deficiencies; diseases of immune dysregulation; congenital defects of phagocyte number, function, or both; defects in intrinsic and innate immunity; autoinflammatory disorders; complement deficiencies; bone marrow failure diseases; and phenocopies of primary immunodeficiency diseases. (See "Inborn errors of immunity (primary immunodeficiencies): Classification".)

Within this classification scheme, primary humoral immunodeficiencies are captured by the "predominantly antibody deficiencies" category. They are characterized by B cell-intrinsic abnormalities that classically result in decreased B cell numbers, impaired antibody production, or both. Because the defects are largely restricted to B cells, primary humoral immunodeficiencies are distinguished separately from other primary immunodeficiency diseases in which abnormal B cell activity plays only a partial role in the disease manifestation. (See "Combined immunodeficiencies" and "Severe combined immunodeficiency (SCID): An overview".)

PRESENTATION OF HUMORAL IMMUNODEFICIENCY — The presence of an underlying primary humoral immunodeficiency should be suspected in a patient with typical sites of infections and types of infectious organisms isolated. Antibodies play an essential role in protection of the sinopulmonary tract and mucosal surfaces. Thus, affected persons commonly develop recurrent otitis media, sinusitis, and pneumonia. Recurrent pneumonias can lead to bronchiectasis, which serves as a negative factor for long-term morbidity and mortality [3]. Classic pathogens consist of polysaccharide-encapsulated bacteria, such as Streptococcus pneumoniae and Haemophilus influenzae [4,5]. Chronic diarrhea associated with Giardia lamblia, Salmonella enterica, Campylobacter jejuni, and rotavirus infections have been observed. Of note, infections are not limited to mucosal surfaces. Invasive infections, such as bacteremia, meningitis, osteomyelitis, and subacute infectious arthritis, can occur due to antibody deficiency and have been attributed to Staphylococcus aureus, Pseudomonas aeruginosa, and Mycoplasma species, in addition to the characteristic encapsulated bacteria [4,5]. Lastly, because of maternal transfer of immunoglobulin G (IgG) to the fetus in utero, a classic presentation for primary humoral immunodeficiency consists of an infant whose susceptibility to infections arises at four to nine months of age, when protective levels of the maternal antibodies have waned (figure 1).

ASSESSMENT OF HUMORAL IMMUNODEFICIENCY — Several laboratory studies are recommended for evaluation of suspected primary humoral immunodeficiency (see "Laboratory evaluation of the immune system"):

Measurement of serum levels of IgG, immunoglobulin A (IgA), and immunoglobulin M (IgM) – The levels obtained must be compared with age-adjusted normal references ranges (table 1). Interpretation of serum IgG levels during the first several months of life should take into consideration the presence or absence of maternal IgG.

Assessment of functional antibody production – In general, this process entails the evaluation of specific antibody titers generated in response to protein and (in children above two years of age) polysaccharide vaccines. (See "Assessing antibody function as part of an immunologic evaluation".)

Immunophenotyping of B cells by flow cytometry – The absence of B cells or certain B cell subsets, such as marginal zone or switched memory B cells, can help to support the presence of underlying primary humoral immunodeficiency. (See "Flow cytometry for the diagnosis of primary immunodeficiencies".)

Genetic testing – Over 45 genetic defects have been identified as causes of primary humoral immunodeficiencies [1,2]. Identification of a disease-causing molecular defect can confirm the presence of primary humoral immunodeficiency. Specific recommendations concerning testing choices remain beyond the scope of this discussion (see "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome" and "Next-generation DNA sequencing (NGS): Principles and clinical applications"), but broad testing may be necessary due to the significant locus heterogeneity for several of the primary humoral immunodeficiency phenotypes (table 2).

NEWBORN SCREENING — Newborn screening for severe B cell deficiencies is also possible by measurement of kappa-deleting recombination excision circles (KRECs) levels in blood and in DNA isolated from dried blood spots (DBS). KRECs are undetectable in primary immunodeficiencies in which B cells are absent or dysfunctional. This screening is under investigation in several countries and states in the US. (See "Newborn screening for primary immunodeficiencies", section on 'Screening for B cell defects'.)

CATEGORIES OF PRIMARY HUMORAL IMMUNODEFICIENCIES — Primary humoral immunodeficiencies have been categorized into four groups by the International Union of Immunological Societies (IUIS) (table 2) [1,2].

Agammaglobulinemia (severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells) — These conditions are identified by very low levels of serum IgG, IgA, and IgM with lack of B cells in the circulation (table 3). They are discussed in detail separately. (See "Agammaglobulinemia".)

CVID phenotype (severe reduction in at least two serum immunoglobulin isotypes with normal or low number of B cells) — The diagnosis of common variable immunodeficiency disease (CVID) is established through fulfillment of specific criteria [6]. Affected individuals have low serum levels of IgG with diminished concentrations of IgA and/or IgM, poor specific antibody responses to immunizations, and deficient isohemagglutinins. Although B cells are present, switched memory B cell numbers and percentages may be low. Other immunodeficiency states must also be excluded. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults" and "Common variable immunodeficiency in children".)

Hyper IgM (severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells) — These primary humoral immunodeficiencies are often characterized by elevated serum levels of IgM (hyper IgM) accompanied by low levels of serum IgG and IgA. The underlying pathophysiology consists of impaired switching of B cells from the IgM isotype to the IgG and IgA isotypes due to defective DNA processing mechanisms. Of note, X-linked hyper-IgM syndrome due to pathogenic variants in the CD40 ligand (CD40LG) gene does not fall into this category since this condition has defects in cellular immunity that convey its placement into the category of combined immunodeficiency. The forms of hyper-IgM syndrome that do fit into this group include autosomal-recessive pathogenic variants in activation-induced cytidine deaminase (AICDA) and uracil DNA glycosylase (UNG). Other class-switch recombination defects include pathogenic variants in INO80 complex (INO80) [7] and mutS homolog 6 (MSH6) [8]. (See "Hyperimmunoglobulin M syndromes" and "The adaptive humoral immune response" and "Normal B and T lymphocyte development", section on 'Maturation of activated B cells'.)

Isotype, light chain, or functional deficiencies with generally normal numbers of B cells — A number of additional primary humoral immunodeficiency diagnoses have been observed. Most of these states are distinguished by abnormalities in immunoglobulin levels or specific antibody production and include the following:

Transient hypogammaglobulinemia of infancy (THI) – THI is classically defined as a delayed physiologic maturation of immunoglobulin production, which produces prolongation of the "physiologic nadir" of hypogammaglobulinemia that is observed in most normal infants at three to six months of age (figure 1). Infants with THI are able to generate protective specific antibody responses. Immunoglobulin levels normalize by three years of age in most children with THI, although serum immunoglobulin concentrations may remain diminished for several years in some children. (See "Transient hypogammaglobulinemia of infancy".)

Selective IgA deficiency – Selective IgA deficiency, the most common immunologic defect in humans, is defined as the presence of serum IgA levels less than 7 mg/dL with normal IgG and IgM levels in individuals four years of age or older. [9,10]. The overwhelming majority of individuals with IgA deficiency are clinically asymptomatic. On occasion, recurrent infections of the respiratory tract or gastrointestinal tract can occur. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis".)

Isolated IgG subclass deficiency – IgG subclass deficiency is a laboratory finding that does not necessarily equate to a clinical disorder. The diagnosis of a clinically significant IgG subclass deficiency requires evidence of antibody dysfunction in the form of recurrent infections and an inadequate response to vaccine challenge. (See "IgG subclass deficiency".)

IgG subclass deficiency with IgA deficiency – This condition is characterized by recurrent bacterial infections in the setting of both IgA and IgG subclass deficiency. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis", section on 'Patients with recurrent infections' and "IgG subclass deficiency", section on 'Associated disorders'.)

Specific antibody deficiency with normal immunoglobulin and B cell levels – Affected individuals usually have normal serum levels of IgG, IgA, and IgM and normal B cell numbers and percentages yet impaired antibody responses to specific antigens, such as immunizations. (See "Specific antibody deficiency".)

Immunoglobulin deficiency due to immunoglobulin heavy chain constant region mu (IGHM) variants and deletions – This agammaglobulinemia (MIM #601495) is associated with genetic variations at 14q32 and is rare (table 2) [11-13]. (See "Agammaglobulinemia", section on 'Autosomal-recessive agammaglobulinemia'.)

Kappa chain deficiency – This condition is associated with autosomal-recessive pathogenic variants in the immunoglobulin kappa constant (IGKC) gene (MIM #614102) [14]. As a result, deficiency of immunoglobulins carrying kappa chains arises. The clinical relevance of this finding remains controversial.

Selective IgM deficiency – This rare deficiency is associated with increased susceptibility to pneumococcal and other serious bacterial infections. (See "Selective IgM deficiency".)

High B cell numbers due to constitutive NFkB activation (CARD11 gain-of-function defect) — Autosomal-dominant pathogenic variants in caspase recruitment domain family member 11 (CARD11) cause a gain-of-function (GOF) variant that results in B cell expansion with nuclear factor kappa B and T cell anergy (BENTA) syndrome (MIM #616452) [15,16]. This disease condition is characterized by polyclonal expansion of B cells. However, specific antibody responses are impaired, resulting in humoral immunodeficiency. Loss-of-function (LOF) pathogenic variants in CARD11 cause a combined immunodeficiency and are discussed separately. (See "Combined immunodeficiencies".)

DIFFERENTIAL DIAGNOSIS — Humoral defects can appear in other primary immunodeficiency diseases that are not restricted to B cells, such as combined immunodeficiencies (see "Combined immunodeficiencies"). Patients with humoral immunodeficiency must therefore be assessed for defects in other immune functions, such as cellular and innate immunity. Secondary causes of humoral immunodeficiency must also be excluded, including:

Medications – Antiseizure medications, such as phenytoin, carbamazepine, valproate, and zonisamide, are well-recognized causes of IgA deficiency [17]. Use of antiinflammatory drugs (eg, gold, penicillamine, sulfasalazine, and hydroxychloroquine) is associated with hypogammaglobulinemia [18]. In addition, many immunosuppressive medications, including cyclosporine, tacrolimus, mycophenolate mofetil, cyclophosphamide, azathioprine, and 6-mercaptopurine, can cause hypogammaglobulinemia. Glucocorticoids may induce hypogammaglobulinemia when administered for extended periods of time [18] (see "Glucocorticoid effects on the immune system"). Finally, several targeted biologic therapies (eg, rituximab and anti-CD19 chimeric antigen receptor T cells) are intended to cause depletion of B cells and can result in hypogammaglobulinemia. (See "Secondary immunodeficiency induced by biologic therapies".)

Losses – Pulmonary losses can occur through the presence of a chylothorax or exudative pleural effusion due to either obstructed lymphatic flow or perturbed intrathoracic pressure. Gastrointestinal losses, due to protein-losing enteropathies such intestinal lymphangiectasia, must be excluded. Nephrotic syndrome can also produce hypogammaglobulinemia through urinary losses. In addition, protein loss can occur with severe atopic dermatitis.

Malnutrition – Poor nutritional status may represent the most common cause of immunodeficiency worldwide, and severe malnutrition is known to result in decreased production of secretory IgA and diminished numbers of B cells [19,20]. Immune function returns to normal when proper nutritional balance is restored.

TREATMENT — Immune globulin replacement therapy is indicated for primary humoral immunodeficiencies that consist of absent or deficient antibody production [21] (see "Immune globulin therapy in primary immunodeficiency"). Recommended use of immune globulin replacement therapy is dictated by placement of the condition within one of six categories:

Agammaglobulinemia due to complete absence of B cells or B cell function – This category matches the International Union of Immunological Societies (IUIS) primary humoral immunodeficiency subcategory of "severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells, agammaglobulinemia" and includes all of the diagnoses contained within it. Immune globulin replacement therapy is fully indicated for these defects due to the severe reduction in all serum immunoglobulin isotypes.

Hypogammaglobulinemia with impaired specific antibody production – The IUIS primary humoral immunodeficiency subcategories of "severe reduction in at least two serum immunoglobulin isotypes with normal or low number of B cells, common variable immunodeficiency (CVID) phenotype" and "severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells, variable immunoglobulin findings" fall into this designation. Immune globulin replacement therapy is advised for this category as well since patients have a severe reduction in at least two serum immunoglobulin isotypes in CVID and in IgG and IgA in class-switch recombination defects.

Normal levels of immunoglobulin and normal B cells but impaired specific antibody production – This category falls within the IUIS primary humoral immunodeficiency subcategory of "isotype, light chain, or functional deficiencies with generally normal numbers of B cells." Immune globulin replacement therapy is not generally recommended as initial treatment for these conditions but may be used if necessary.

Hypogammaglobulinemia and normal-quality antibody responses – Transient hypogammaglobulinemia of infancy (THI) also falls within the IUIS primary humoral immunodeficiency subcategory of "isotype, light chain, or functional deficiencies with generally normal numbers of B cells." Immune globulin replacement therapy is not generally recommended for conditions within this category.

Normal serum IgG levels, normal-quality antibody responses, and decreased serum level of one or more IgG subclasses – The IgG subclass deficiencies also fall within the IUIS primary humoral immunodeficiency subcategory of "isotype, light chain, or functional deficiencies with generally normal numbers of B cells." Guidelines do not recommend IgG replacement therapy for these diagnoses, but the restriction remains controversial.

Recurrent infections due to an unknown immune mechanism – This category does not apply to primary humoral immunodeficiencies, since all primary humoral immunodeficiencies fall into one of the other five categories.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY

Definition – Primary humoral immunodeficiencies (table 2) are recognized as predominantly antibody deficiencies that are distinguished separately from other primary immunodeficiency diseases in which humoral abnormalities play only a partial role in the disease manifestation. (See 'Introduction' above.)

Presentation – Antibody deficiency classically presents with recurrent infections of the sinopulmonary tract by polysaccharide-encapsulated pathogens, such as Streptococcus pneumoniae and Haemophilus influenzae. Chronic infectious diarrhea and invasive infections can also occur. The classic age at presentation is four to nine months. (See 'Presentation of humoral immunodeficiency' above.)

Diagnostic evaluation – Persons with suspected primary humoral immunodeficiencies should be evaluated by measurements of serum immunoglobulin levels, assessment of antibody responses to specific antigens, characterization of B cell phenotypes by flow cytometry, and (in some cases) genetic testing. (See 'Assessment of humoral immunodeficiency' above.)

Differential diagnosis – In order to establish a diagnosis of primary humoral immunodeficiency, other primary immunodeficiencies and secondary causes of humoral immunodeficiency must be excluded. (See 'Differential diagnosis' above.)

TreatmentImmune globulin replacement therapy is indicated for most primary humoral immunodeficiencies in accordance with recommendations from expert guidelines. (See 'Treatment' above.)

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