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Overview of Immunodeficiency Disorders

By

James Fernandez

, MD, PhD, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University

Reviewed/Revised Jan 2023
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Topic Resources

Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies are genetically determined and can be hereditary; secondary immunodeficiencies are acquired and much more common.

  • Whether a primary or secondary immunodeficiency is suspected

  • For primary immunodeficiency, which component of the immune system is thought to be deficient

Primary Immunodeficiencies

These disorders are genetically determined; they may occur alone or as part of a syndrome. In 2022, the International Union of Immunological Societies reported that 485 inborn errors of immunity have been linked to primary immunodeficiency disorders (1 Primary immunodeficiency references Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more ). Despite advances in genetic discoveries, it is thought that only about 20 to 30% of current primary immunodeficiencies have a definable genetic mutation.

Primary immunodeficiencies typically manifest during infancy and childhood as abnormally frequent (recurrent) or unusual infections. About 70% of patients are < 20 years at onset; because transmission is often X-linked, 60% are male. Overall incidence of symptomatic disease is about 1/280 people.

Primary immunodeficiencies are classified by the main component of the immune system that is deficient, absent, or defective:

Primary immunodeficiency syndromes are genetically determined immunodeficiencies with immune and nonimmune defects. Nonimmune manifestations are often more easily recognized than those of the immunodeficiency. Examples are ataxia-telangiectasia Ataxia-Telangiectasia Ataxia-telangiectasia results from a DNA repair defect that frequently results in humoral and cellular immunodeficiency; it causes progressive cerebellar ataxia, oculocutaneous telangiectasias... read more Ataxia-Telangiectasia , cartilage-hair hypoplasia, DiGeorge syndrome DiGeorge Syndrome DiGeorge syndrome is thymic and parathyroid hypoplasia or aplasia leading to T-cell immunodeficiency and hypoparathyroidism. Infants with DiGeorge syndrome have low-set ears, midline facial... read more , hyper-IgE syndrome Hyper-IgE Syndrome Hyper-IgE syndrome is a hereditary combined B- and T-cell immunodeficiency characterized by recurrent staphylococcal abscesses of the skin, sinopulmonary infections, and severe pruritic eosinophilic... read more , and Wiskott-Aldrich syndrome Wiskott-Aldrich Syndrome Wiskott-Aldrich syndrome is an immunodeficiency disorder that involves a combined B- and T-cell defect and is characterized by recurrent infection, eczema, and thrombocytopenia. (See also Overview... read more . Despite the presence of immunodeficiencies, some patients also develop autoimmune disorders Autoimmune Disorders In autoimmune disorders, the immune system produces antibodies to an endogenous antigen (autoantigen). The following types of hypersensitivity reactions may be involved: Type II: Antibody-coated... read more .

Immunodeficiency typically manifests as recurrent infections. The age at which recurrent infections began provides a clue as to which component of the immune system is affected. Other characteristic findings tentatively suggest a clinical diagnosis (see Characteristic Clinical Findings in Some Primary Immunodeficiency Disorders Characteristic Clinical Findings in Some Primary Immunodeficiency Disorders Characteristic Clinical Findings in Some Primary Immunodeficiency Disorders ). However, tests are needed to confirm a diagnosis of immunodeficiency (see Initial and Additional Laboratory Tests for Immunodeficiency Initial and Additional Laboratory Tests for Immunodeficiency Initial and Additional Laboratory Tests for Immunodeficiency ). If clinical findings or initial tests suggest a specific disorder of immune cell or complement function, additional tests Additional testing Immunodeficiency typically manifests as recurrent infections. However, recurrent infections are more likely to have causes other than immunodeficiency (eg, inadequate treatment, resistant organisms... read more are indicated for confirmation (see Specific and Advanced Laboratory Tests for Immunodeficiency Specific and Advanced Laboratory Tests for Immunodeficiency* Specific and Advanced Laboratory Tests for Immunodeficiency* ).

Humoral immunity deficiencies

Humoral immunity deficiencies (B-cell defects) that cause antibody deficiencies account for 50 to 60% of primary immunodeficiencies (see table Humoral Immunity Deficiencies Humoral Immunity Deficiencies Humoral Immunity Deficiencies ). Serum antibody titers decrease, predisposing to bacterial infections.

The most common B-cell disorder is

Selective IgA deficiency is the most common B-cell disorder, but many patients are asymptomatic. Common variable immunodeficiency (CVID) is the most common symptomatic immunodeficiency.

Table

Cellular immunity deficiencies

Cellular immunity deficiencies (T-cell defects) account for about 5 to 10% of primary immunodeficiencies and predispose to infection by viruses, Pneumocystis jirovecii Pneumocystis jirovecii Pneumonia Pneumocystis jirovecii, an atypical fungus, is a common cause of pneumonia in immunosuppressed patients, especially in those infected with human immunodeficiency virus (HIV) and in those... read more <i >Pneumocystis jirovecii</i> Pneumonia , fungi, other opportunistic organisms, and many common pathogens (see table Cellular Immunity Deficiencies Cellular Immunity Deficiencies Cellular Immunity Deficiencies ). T-cell disorders also cause Ig deficiencies because the B- and T-cell immune systems are interdependent.

The most common T-cell disorders are

Secondary natural killer cell defects can occur in patients who have various other primary or secondary immunodeficiencies, frequently in those with cancer or autoimmune disease and in those taking certain medications (4, 5 Primary immunodeficiency references Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more ).

For diagnostic evaluation of cellular immunity deficiencies, see tables and .

Table

Combined humoral and cellular immunity deficiencies

Combined humoral and cellular immunity deficiencies (B- and T-cell defects) account for about 20% of primary immunodeficiencies (see table Combined Humoral and Cellular Immunity Deficiencies Combined Humoral and Cellular Immunity Deficiencies Combined Humoral and Cellular Immunity Deficiencies ).

The most important form is

In some forms of combined immunodeficiency (eg, purine nucleoside phosphorylase deficiency), Ig levels are normal or elevated, but because of inadequate T-cell function, antibody formation is impaired.

For diagnostic evaluation of combined humoral and cellular immunodeficiencies, see table .

Table

Phagocytic cell defects

Phagocytic cell defects account for 10 to 15% of primary immunodeficiencies; the ability of phagocytic cells (eg, monocytes, macrophages, granulocytes such as neutrophils and eosinophils) to kill pathogens is impaired (see table Phagocytic Cell Defects Phagocytic Cell Defects Phagocytic Cell Defects ). Cutaneous staphylococcal and gram-negative infections are characteristic.

The most common (although still rare) phagocytic cell defects are

For diagnostic evaluation of phagocytic cell defects, see tables and .

Table

Complement deficiencies

Complement deficiencies are rare ( 2% of primary immunodeficiencies); they include isolated deficiencies of complement components or inhibitors and may be hereditary or acquired (see table Complement Deficiencies Complement Deficiencies Complement Deficiencies ). Hereditary deficiencies are autosomal recessive except for deficiencies of C1 inhibitor, which is autosomal dominant, and properdin, which is X-linked. The deficiencies result in defective opsonization, phagocytosis, and lysis of pathogens and in defective clearance of antigen-antibody complexes.

The most serious consequences are

  • Recurrent infection, which is due to defective opsonization

  • Autoimmune disorders (eg, systemic lupus erythematosus, glomerulonephritis), which are due to defective clearance of antigen-antibody complexes

Complement deficiencies can affect the classical and/or alternate pathways of the complement system Complement System The complement system is an enzyme cascade that helps defend against infection via activation of a local inflammatory response. Many complement proteins occur in serum as inactive enzyme precursors... read more . The alternate pathway shares C3 and C5 through C9 with the classical pathway but has additional components: factor D, factor B, properdin (P), and regulatory factors H and I.

For diagnostic evaluation of complement deficiencies, see tables and .

Table

Primary immunodeficiency references

  • 1. Tangye SG, Al-Herz W, Bousfiha A, et al: Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee [published online ahead of print, 2022 Jun 24]. J Clin Immunol 2022;1–35. doi:10.1007/s10875-022-01289-3

  • 2. Chinn IK, Chan AY, Chen K, et al: Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: A working group report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol 145(1):46–69, 2020. doi: 10.1016/j.jaci.2019.09.009

  • 3. Leonardi L, Rivalta B, Cancrini C, et al: Update in primary immunodeficiencies. Acta Biomed 91(11-S):e2020010, 2020. doi: 10.23750/abm.v91i11-S.10314

  • 4. Moon WY, Powis SJ: Does natural killer cell deficiency (NKD) increase the risk of cancer? NKD may increase the risk of some virus induced cancer. Front Immunol 10:1703, 2019. Published 2019 Jul 19. doi:10.3389/fimmu.2019.01703

  • 5. Schleinitz N, Vély F, Harlé JR, Vivier E: Natural killer cells in human autoimmune diseases. Immunology 131(4):451–458, 2010. doi:10.1111/j.1365-2567.2010.03360.x

Secondary Immunodeficiencies

Secondary immunodeficiency also occurs among critically ill, older, or hospitalized patients. Prolonged serious illness may impair immune responses; impairment is often reversible if the underlying illness resolves. Rarely, prolonged exposure to toxic substances (eg, certain pesticides, benzene) can be immunosuppressive.

Table
Table

Immunodeficiency can result from loss of serum proteins (particularly IgG and albumin) through the following:

  • The kidneys in nephrotic syndrome

  • The skin in severe burns or dermatitis

  • The gastrointestinal (GI) tract in enteropathy

Enteropathy may also lead to lymphocyte loss, resulting in lymphopenia.

Treatment focuses on the underlying disorder; for example, a diet high in medium-chain triglycerides may decrease loss of immunoglobulins (Igs) and lymphocytes from the gastrointestinal tract and be remarkably beneficial.

If a specific secondary immunodeficiency disorder is suspected clinically, testing should focus on that disorder (eg, diabetes, HIV infection, cystic fibrosis, primary ciliary dyskinesia).

Geriatrics Essentials: Immunodeficiency

Some decrease in immunity occurs with aging. For example, in older adults, the thymus tends to produce fewer naive T cells; thus, fewer T cells are available to respond to new antigens. The total number of T cells does not decrease (because of oligoclonality), but these cells can recognize only a limited number of antigens.

Signal transduction (transmission of antigen-binding signal across the cell membrane into the cell) is impaired, making T cells less likely to respond to antigens. Also, helper T cells may be less likely to signal B cells to produce antibodies.

The number of neutrophils does not decrease, but these cells become less effective in phagocytosis and microbicidal action.

Undernutrition, common among older adults, impairs immune responses. Calcium, zinc, and vitamin E are particularly important to immunity. Risk of calcium deficiency Overview of Disorders of Calcium Concentration Calcium (Ca) is required for the proper functioning of muscle contraction, nerve conduction, hormone release, and blood coagulation. In addition, proper calcium concentration is required for... read more is increased in older adults, partly because with aging, the intestine becomes less able to absorb calcium. Also, the elderly may not ingest enough calcium in their diet. Zinc deficiency Zinc Deficiency Zinc (Zn) is contained mainly in bones, teeth, hair, skin, liver, muscle, leukocytes, and testes. Zinc is a component of several hundred enzymes, including many nicotinamide adenine dinucleotide... read more Zinc Deficiency is very common among adults living in institutional settings and homebound patients.

Key Points

  • Secondary (acquired) immunodeficiencies are much more common than primary (genetic) immunodeficiencies.

  • Primary immunodeficiencies can affect humoral immunity (most commonly), cellular immunity, both humoral and cellular immunity, phagocytic cells, or the complement system.

  • Patients who have primary immunodeficiencies may have nonimmune manifestations that can be recognized more easily than the immunodeficiencies.

  • Immunity tends to decrease with aging partly because of age-related changes; also, conditions that impair immunity (eg, certain disorders, use of certain drugs) are more common among older adults.

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