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.
Evaluation of immunodeficiency includes history, physical examination, and immune function testing. Testing varies based on the following:
Whether a primary or secondary immunodeficiency is suspected
For primary immunodeficiency, which component of the immune system is thought to be deficient
Первинні імунодефіцити
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). 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:
As more molecular defects are defined, classifying immunodeficiencies by their molecular defects will become more appropriate (2).
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, cartilage-hair hypoplasia, DiGeorge syndrome, hyper-IgE syndrome, and Wiskott-Aldrich syndrome. Despite the presence of immunodeficiencies, some patients also develop autoimmune disorders.
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). However, tests are needed to confirm a diagnosis of immunodeficiency (see 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 are indicated for confirmation (see Specific and Advanced Laboratory Tests for Immunodeficiency).
Treatment and prognosis of primary immunodeficiency disorders depend on the specific disorder (3).
Дефіцити гуморального імунітету
Humoral immunity deficiencies (B-cell defects) that cause antibody deficiencies account for 50 to 60% of primary immunodeficiencies (see table 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.
For diagnostic evaluation of humoral immunity deficiencies, see Approach to the Patient With Suspected Immunodeficiency and table Specific and Advanced Laboratory Tests for Immunodeficiency.
Дефіцити гуморального імунітету
Disorder | Inheritance | Genes Affected | Clinical Findings |
|---|---|---|---|
Variable | BAFFR, CTLA4, CR2, GATA2, ICOS, IL21, JAK3, NKFKB2, PIK3CD, RAG2, STAT3, TACI | Recurrent sinopulmonary infections, autoimmune disorders (eg, immune thrombocytopenia, autoimmune hemolytic anemia), malabsorption, giardiasis, granulomatous interstitial lung disease, nodular lymphoid hyperplasia of the GI tract, bronchiectasis, lymphocytic interstitial pneumonia, splenomegaly; in 10%, gastric carcinoma and lymphoma Usually diagnosed in patients aged 20–40 years | |
Autosomal recessive | AID, UNG | Similar to X-linked hyper-IgM syndrome but with lymphoid hyperplasia No leukopenia | |
Autosomal recessive | CD40 | Similar to X-linked hyper-IgM syndrome Lymphoid hypoplasia, neutropenia | |
X-linked | CD40 ligand (CD40L) | Similar to X-linked agammaglobulinemia (eg, recurrent pyogenic bacterial sinopulmonary infections) but greater frequency of Pneumocystis jirovecii pneumonia, cryptosporidiosis, severe neutropenia, and lymphoid hypoplasia | |
Unknown | — | Recurrent sinopulmonary infections Sometimes atopic manifestations (eg, atopic dermatitis, asthma, chronic rhinitis) Can occur in mild, moderate, severe, and memory phenotypes | |
Unknown | In some cases, TACI | Most often asymptomatic Recurrent sinopulmonary infections, diarrhea, allergies (including anaphylactic transfusion reactions [rare]), autoimmune disorders (eg, celiac disease, inflammatory bowel disease, SLE, chronic active hepatitis) | |
Unknown | — | Usually asymptomatic Sometimes recurrent sinopulmonary or GI infections, candidiasis, meningitis | |
X-linked | BTK | Recurrent sinopulmonary and skin infections during infancy, transient neutropenia, lymphoid hypoplasia Persistent CNS infections resulting from live-attenuated oral polio vaccine, echoviruses, or coxsackieviruses Increased risk of infectious arthritis, bronchiectasis, and certain cancers | |
AID = activation-dependent (induced) cytidine deaminase; BAFFR = B-cell activating factor receptor; BTK = Bruton tyrosine kinase; C = complement; CAML = calcium-modulator and cyclophilin ligand; CD = clusters of differentiation; CNS = central nervous system; CR2= complement receptor 2,;CTLA4 = cytotoxic T-lymphocyte-associated protein 4; GATA2= GATA binding protein 2; GI = gastrointestinal; ICOS = inducible T-cell co-stimulator; IL21 = interleukin 21 ; JAK3= Janus kinase 3 ; NKFKB2 = nuclear factor kappa B subunit 2; PIK3CD = phosphatidyl 3-kinase catalytic subunit delta; RAG2= recombination activating 2 gene ; SLE = systemic lupus erythematosus; STAT3 = signal transducer and activator of transcription 3; TACI = transmembrane activator and CAML interactor; UNG = uracil DNA glycosylase. | |||
Дефіцити клітинного імунітету
Cellular immunity deficiencies (T-cell defects) account for about 5 to 10% of primary immunodeficiencies and predispose to infection by viruses, Pneumocystis jirovecii, fungi, other opportunistic organisms, and many common pathogens (see table 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
Primary natural killer cell defects, which are very rare, may predispose to viral infections (specifically herpesvirus infection) and tumors.
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).
For diagnostic evaluation of cellular immunity deficiencies, see tables Initial and Additional Laboratory Tests for Immunodeficiency and Specific and Advanced Laboratory Tests for Immunodeficiency.
Дефіцити клітинного імунітету
Disorder | Inheritance | Gene Affected | Clinical Findings |
|---|---|---|---|
Autosomal dominant or recessive | STAT1 (dominant) AIRE (recessive) | Persistent or recurrent candidal infections, onychomycosis, autosomal recessive autoimmune polyendocrinopathy–candidosis-ectodermal dystrophy (with hypoparathyroidism and adrenal insufficiency) | |
Autosomal dominant | Genes at chromosomal region 22q11.2 Genes at chromosome 10p13 | Characteristic facial appearance with low-set ears, a congenital heart disorder (eg, aortic arch abnormalities), thymic hypoplasia or aplasia, hypoparathyroidism with hypocalcemic tetany, recurrent infections, developmental delay | |
X-linked | SH2D1A (type 1) XIAP (type 2) | Asymptomatic until onset of Epstein-Barr virus infection, then fulminant or fatal infectious mononucleosis with liver failure, B-cell lymphomas, splenomegaly, aplastic anemia | |
Autosomal recessive | ZAP-70 | Common and opportunistic infections No CD8 cells | |
AIRE = autoimmune regulator; CD = clusters of differentiation; SH2D1A = SH2 domain containing 1A; STAT = signal transducer and activator of transcription; XIAP = X-linked inhibitor of apoptosis. | |||
Комбіновані дефіцити гуморального та клітинного імунітету
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).
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 Specific and Advanced Laboratory Tests for Immunodeficiency.
Комбіновані дефіцити гуморального та клітинного імунітету
Disorder | Inheritance | Gene Affected | Clinical Findings |
|---|---|---|---|
Autosomal recessive | ATM | Ataxia, telangiectasias, recurrent sinopulmonary infections, endocrine abnormalities (eg, gonadal dysgenesis, testicular atrophy, diabetes mellitus), increased risk of cancer | |
Cartilage-hair hypoplasia | Autosomal recessive | RMRP | Short-limbed dwarfism, common and opportunistic infections |
Combined immunodeficiency with inadequate but not absent T-cell function and normal or elevated immunoglobulins | Autosomal recessive or X-linked | NEMO | Common and opportunistic infections, lymphopenia, lymphadenopathy, hepatosplenomegaly, skin lesions resembling those of Langerhans cell histiocytosis in some patients |
Autosomal dominant or recessive | STAT3 (dominant) TYK2, DOCK8 (recessive) | Sinopulmonary infections; staphylococcal abscesses of skin, lungs, joints, and viscera; pulmonary pneumatoceles; pruritic dermatitis; coarse facial features; delayed shedding of baby teeth; osteopenia; recurrent fractures; tissue and blood eosinophilia | |
MHC antigen deficiencies | Autosomal recessive | Various including, RFX: RFXANK, RFX5, and RFXAP | Common and opportunistic infections |
Autosomal recessive or X-linked | JAK3, PTPRC (CD45), RAG1, RAG2 (autosomal recessive) IL-2RG(X-linked) | Oral candidiasis, Pneumocystis jirovecii pneumonia, diarrhea before 6 months, failure to thrive, graft vs host disease, absent thymic shadow, lymphopenia, bone abnormalities (in ADA deficiency), exfoliative dermatitis as part of Omenn syndrome* | |
X-linked recessive | WASP | Typically, pyogenic and opportunistic infections, eczema, thrombocytopenia Possibly gastrointestinal bleeding (eg, bloody diarrhea), recurrent respiratory infections, cancer (in 10% of patients > 10 years), varicella-zoster virus infection, herpesvirus infection | |
* Omenn syndrome is an autosomal recessive form of severe SCID causing erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, eosinophilia, hepatosplenomegaly, and elevated serum IgE levels. | |||
ADA =adenosine deaminase; ATM = ataxia telangiectasia–mutated; DOCK = dedicator of cytokinesis; IL-2RG = IL-2 receptor gamma; JAK = Janus kinase; MHC = major histocompatibility complex; NEMO = nuclear factor–kappa-B essential modulator; PTPRC = protein tyrosine phosphatase, receptor type, C; RAG = recombination activating gene; RFX = regulatory factor X; RFXANK= RFX containing ankyrin repeats; RFXAP = RFX-associated protein; RMRP = ribonuclease mitochondrial RNA-processing; SCID = severe combined immunodeficiency; STAT = signal transducer and activator of transcription; TYK = tyrosine kinase; WASP = Wiskott-Aldrich syndrome protein. | |||
Дефекти фагоцитів
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). Cutaneous staphylococcal and gram-negative infections are characteristic.
The most common (although still rare) phagocytic cell defects are
Leukocyte adhesion deficiency (types 1 and 2)
For diagnostic evaluation of phagocytic cell defects, see tables Initial and Additional Laboratory Tests for Immunodeficiency and Specific and Advanced Laboratory Tests for Immunodeficiency.
Дефекти фагоцитів
Disorder | Inheritance | Genes Affected | Clinical Findings |
|---|---|---|---|
Autosomal recessive | LYST (CHS1) | Oculocutaneous albinism, recurrent infections, fever, jaundice, hepatosplenomegaly, lymphadenopathy, neuropathy, pancytopenia, bleeding diathesis | |
X-linked or autosomal recessive | gp91phox (CYBB; X-linked) p22phox, p47phox, p67phox (autosomal recessive) | Granulomatous lesions in the lungs, liver, lymph nodes, and gastrointestinal and genitourinary tracts (causing obstruction); lymphadenitis; hepatosplenomegaly; skin, lymph node, lung, liver, and perianal abscesses; osteomyelitis; pneumonia; staphylococcal, gram-negative, and aspergillus infections | |
Autosomal recessive | ITGB2 gene, encoding CD18 of beta-2 integrins (type 1) GDP-fucose transporter gene (type 2) | Soft-tissue infections, periodontitis, poor wound healing, delayed umbilical cord detachment, leukocytosis, no formation of pus Developmental delay (type 2) | |
Mendelian susceptibility to mycobacterial disease (MSMD) | Autosomal dominant or recessive | Defects in genes encoding the IFN-gamma receptor, IL-12, or the IL-12 receptor | Mycobacterial infections Varying clinical severity based on genetic defect |
Cyclic neutropenia | Autosomal dominant | ELA2 | Pyogenic bacterial infections during recurrent episodes of neutropenia (eg, every 14 to 35 days) |
CD = clusters of differentiation; CHS = Chédiak-Higashi syndrome; CYBB = cytochrome b-245, beta polypeptide; ELA = elastase; GDP = glucose diphosphate; gp = glycoprotein; IFN = interferon; IL = interleukin; ITGB2 = integrin beta-2; LYST = lysosomal transporter. | |||
Дефіцити комплементу
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). 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
A deficiency in a complement regulatory protein, C1 inhibitor, causes hereditary angioedema.
Complement deficiencies can affect the classical and/or alternate pathways of the complement system. 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 Initial and Additional Laboratory Tests for Immunodeficiency and Specific and Advanced Laboratory Tests for Immunodeficiency.
Дефіцити комплементу
Disorder | Inheritance | Clinical Findings |
|---|---|---|
C1 | Autosomal recessive | |
C2 | Autosomal recessive | SLE, recurrent pyogenic infections with encapsulated bacteria (especially pneumococcal) that start in early childhood, other autoimmune disorders (eg, glomerulonephritis, autoimmune myositis , vasculitis, IgA-associated vasculitis, Hodgkin lymphoma) |
C3 | Autosomal recessive | Recurrent pyogenic infections with encapsulated bacteria that start at birth, glomerulonephritis, other antigen-antibody complex disorders, sepsis |
C4 | Autosomal recessive | SLE, other autoimmune disorders (eg, IgA nephropathy, progressive systemic sclerosis, IgA-associated vasculitis, type 1 diabetes mellitus, autoimmune hepatitis) |
C5, C6, C7, C8, C9 (membrane attack complex) | Autosomal recessive | Recurrent Neisseria meningitidis and disseminated N. gonorrhoeae infections |
Complement deficiencies in the MBL pathway | ||
MBL | Autosomal recessive | Recurrent pyogenic infections with encapsulated bacteria that start at birth; unexplained sepsis; increased severity of infection in secondary immunodeficiencies due to corticosteroid use, cystic fibrosis, or chronic lung disorders |
MASP-2 | Unknown | Autoimmune disorders (eg, inflammatory bowel disease, erythema multiforme), recurrent pyogenic infections with encapsulated bacteria (eg, Streptococcus pneumoniae) |
Complement deficiencies in the alternative pathway | ||
Factor B | Autosomal recessive | Pyogenic infections |
Factor D | Autosomal | Pyogenic infections |
Properdin | X-linked | Increased risk of fulminant neisserial infection |
Complement regulatory protein deficiencies | ||
C1 inhibitor | Autosomal dominant | |
Factor I | Autosomal codominant | Same as C3 deficiency |
Factor H | Autosomal codominant | Same as C3 deficiency |
Decay accelerating factor | Autosomal recessive | |
Complement receptor (CR) deficiencies | ||
CR1 | Acquired | Secondary finding in immune (antigen-antibody) complex–mediated disease |
CR3 | Autosomal recessive | Leukocyte adhesion deficiency (recurrent Staphylococcus aureus and Pseudomonas aeruginosa infections) |
C = complement; MASP = mannose-binding lectin-associated serine protease; MBL = mannose-binding lectin; SLE = systemic lupus erythematosus. | ||
Довідкові матеріали щодо первинного імунодефіциту
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
Вторинні імунодефіцити
Causes (see table Some Disorders That Cause Secondary Immunodeficiency) include
Systemic disorders (eg, diabetes, undernutrition, HIV infection)
Immunosuppressive treatments (eg, cytotoxic chemotherapy, bone marrow ablation before transplantation, radiation therapy)
Prolonged serious illness
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.
Деякі захворювання, що викликають вторинні імунодефіцити
Category | Examples |
|---|
Деякі лікарські засоби, що спричиняють імуносупресію
Class | Examples |
|---|
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).
Засади геріатрії: імунодефіцит
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.
Certain disorders (eg, diabetes, chronic kidney disease, undernutrition), which are more common among older adults, and certain therapies (eg, immunosuppressants, immunomodulatory drugs and treatments), which the elderly are more likely to use, can also impair immunity.
Ключові моменти
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.
