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Overview of Immunodeficiency Disorders

By

James Fernandez

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

Last full review/revision Apr 2021| Content last modified Apr 2021
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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 2019, the International Union of Immunological Sciences reported that 354 inborn errors of immunity and 430 genes 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 ).The molecular basis for about 80% is known.

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 deficiency; it causes progressive cerebellar ataxia, oculocutaneous telangiectasias, and... read more , 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 results from a combined B- and T-cell defect and is characterized by recurrent infection, eczema, and thrombocytopenia. (See also Overview of Immunodeficiency Disorders... 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 hypersensitivity reactions may be involved: Type II: Antibody-coated cells... 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 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 ). 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 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 ). 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 (see Specific and Advanced Laboratory Tests for Immunodeficiency Specific and Advanced Laboratory Tests for Immunodeficiency* 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 ).

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 Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more ). Serum antibody titers decrease, predisposing to bacterial infections.

The most common B-cell disorder is

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Cellular immunity deficiencies

The most common T-cell disorders are

Primary natural killer cell defects, which are very rare, may predispose to viral infections and tumors. Secondary natural killer cell defects can occur in patients who have various other primary or secondary immunodeficiencies.

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Combined humoral and cellular immunity deficiencies

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 Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more ). Cutaneous staphylococcal and gram-negative infections are characteristic.

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

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Complement deficiencies

Complement deficiencies are rare ( 2%); they include isolated deficiencies of complement components or inhibitors and may be hereditary or acquired (see table 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. Many complement proteins occur in serum as inactive enzyme precursors (zymogens); others reside on cell surfaces... 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.

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Primary immunodeficiency references

  • 1. Tangye SG, Al-Herz W, Bousfiha A, et al: Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 40(1):24–64, 2020. doi: 10.1007/s10875-019-00737-x

  • 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

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.

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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

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 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 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.

Drugs Mentioned In This Article

Drug Name Select Trade
MEDROL
CELLCEPT
IMURAN
NEORAL, SANDIMMUNE
JAKAFI
ACTEMRA
LAMICTAL
SIMULECT
ENBREL
REMICADE
HUMIRA
PROGRAF
RAYOS
AFINITOR
Brodalumab
RAPAMUNE
DILANTIN
ORENCIA
RITUXAN
KINERET
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