Diseases of the Immune System
Diseases of the Immune System
Immune disease can arise when self-tolerance breaks down, a protective response causes tissue injury, one lymphoid clone expands, or an immune compartment cannot perform its task. Laboratory evaluation connects patterns in blood cells, antibodies, complement, proteins, and functional tests to the affected mechanism.1
These disease patterns build on immune-system physiology and immunoglobulins and antigen-antibody interactions and complement.
Autoimmunity and loss of tolerance
Self-tolerance limits responses against the body’s own antigens. Central tolerance acts during lymphocyte development in the thymus and bone marrow. Peripheral tolerance controls mature lymphocytes through inadequate costimulation, inhibitory receptors, regulatory T cells, anergy, deletion, and other suppressive mechanisms. Autoimmune disease can follow failure at one or more of these checkpoints.1
Genetic susceptibility changes which self-peptides are presented and how lymphocytes are regulated. Infection or tissue injury can expose previously sequestered antigens, create cross-reactive microbial responses, or broaden an established response to additional self-epitopes. Modified proteins can also become antibody targets. Antibodies to citrullinated proteins in rheumatoid arthritis are one laboratory example. These influences vary among diseases and patients.
Autoimmune injury often combines several effector mechanisms. Antibody can promote cell clearance, block or stimulate a receptor, form tissue-depositing immune complexes, or recruit complement and Fc-receptor-bearing cells. Autoreactive T cells and innate inflammatory pathways can add direct tissue injury.
Systemic autoimmune patterns
Autoantibodies support a disease association when they fit the clinical and laboratory pattern. Their sensitivity and specificity depend on the antigen, assay, cutoff, and population.
| Disease pattern | Associated laboratory findings | Main interpretation |
|---|---|---|
| Systemic lupus erythematosus (SLE) | Antinuclear antibody (ANA); anti-double-stranded DNA and anti-Sm; low C3 or C4; cytopenias; proteinuria or active urine sediment | ANA is sensitive. Anti-dsDNA and anti-Sm carry greater specificity. Complement, renal findings, and blood counts help define organ involvement and activity.2 |
| Antiphospholipid syndrome (APS) | Lupus anticoagulant, anticardiolipin IgG or IgM, and anti-beta-2-glycoprotein I IgG or IgM | Persistent phospholipid-dependent antibodies support APS classification when a qualifying clinical criterion is present.3 |
| Rheumatoid arthritis | Rheumatoid factor and anti-citrullinated protein antibodies, commonly reported as anti-CCP | Anti-CCP is generally more specific. Serology is interpreted with joint findings and inflammatory markers. |
| Sjögren disease | Anti-SS-A/Ro, with or without anti-SS-B/La; ANA and rheumatoid factor can also occur | Anti-SS-A/Ro is the stronger serologic association. An isolated anti-SS-B/La result has limited specificity. |
| Systemic sclerosis | Anti-topoisomerase I, anticentromere, or anti-RNA polymerase III antibodies | Each antibody is associated with a clinical phenotype and risk pattern. The antibody result supports classification and surveillance decisions. |
| Mixed connective tissue disease and inflammatory myopathies | High-titer anti-U1-RNP in mixed connective tissue disease; myositis-specific and myositis-associated antibodies in inflammatory myopathies | Antibodies support classification within a compatible clinical phenotype.1 |
| ANCA-associated vasculitis | Proteinase 3 antibody or myeloperoxidase antibody | PR3 is associated most strongly with granulomatosis with polyangiitis; MPO is associated with microscopic polyangiitis and an ANCA-positive subset of eosinophilic granulomatosis with polyangiitis.4,5 |
The 2019 European League Against Rheumatism and American College of Rheumatology SLE classification criteria use ANA positivity at least once at a titer of 1:80 or greater on HEp-2 cells, or an equivalent assay, as an entry criterion. Weighted clinical and immunologic findings follow. Clinical diagnosis uses the full presentation, while classification criteria define comparable groups for research.2
SLE can produce immune-complex renal injury, cytopenias, and antiphospholipid antibodies. A useful laboratory assessment can include CBC and platelet count, creatinine or estimated glomerular filtration rate, urinalysis with urine protein assessment, ANA, anti-dsDNA, anti-Sm, C3, C4, and antiphospholipid antibody testing selected for the presentation. Serial anti-dsDNA and complement results can help monitor some patients when the changes are consistent with their established disease pattern.
The 2023 APS research classification criteria require at least one qualifying clinical criterion and one qualifying laboratory criterion. Persistent results are documented on at least 2 occasions 12 weeks or more apart. By enzyme-linked immunosorbent assay, moderate anticardiolipin or anti-beta-2-glycoprotein I levels are 40 to 79 U and high levels are 80 U or greater. A lupus anticoagulant result depends on a validated phospholipid-dependent testing process and careful assessment of anticoagulant interference.3
For suspected granulomatosis with polyangiitis or microscopic polyangiitis, the revised international consensus supports high-quality PR3-ANCA and MPO-ANCA immunoassays as primary tests. Indirect immunofluorescence or a second antigen-specific assay can resolve selected low-positive, discordant, or strongly suspected cases. Disease probability comes from the antibody specificity, result strength, organs involved, and other findings. A negative PR3-ANCA, MPO-ANCA, or ANCA result can occur in ANCA-associated vasculitis.4,5
Organ-specific autoimmune patterns
The most useful result pairs an organ-focused antibody with biochemical, functional, imaging, or tissue evidence of disease.1
| Disease or organ system | Useful antibody or laboratory pattern | Interpretation limit |
|---|---|---|
| Hashimoto thyroiditis | Anti-thyroid peroxidase, with anti-thyroglobulin as an additional association | Interpret with thyroid-stimulating hormone and free thyroxine. |
| Graves disease | TSH-receptor antibody; stimulating-antibody bioassays assess stimulatory activity | Receptor-binding assays can detect stimulating and blocking antibodies together. Thyroid function establishes the biochemical state. |
| Type 1 diabetes | Insulin, GAD65, IA-2, and ZnT8 autoantibodies | Multiple positive autoantibodies increase the probability of autoimmune beta-cell disease. Antibody-negative disease still occurs.6 |
| Celiac disease | IgA anti-tissue transglutaminase with total IgA; IgG-based testing for IgA deficiency | Testing during adequate gluten consumption preserves sensitivity. Serology is interpreted with the diagnostic pathway and, when indicated, tissue findings.7 |
| Autoimmune hepatitis and primary biliary cholangitis | ANA and smooth-muscle antibody for type 1 autoimmune hepatitis; anti-LKM1 or anti-LC1 for type 2; antimitochondrial antibody for primary biliary cholangitis | Biochemical, viral, medication, and histologic findings establish the final interpretation. |
| Myasthenia gravis and anti-GBM disease | Acetylcholine-receptor antibody, followed by selected MuSK or LRP4 testing; anti-GBM antibody with linear IgG on renal immunofluorescence | Each result supports a compatible neuromuscular or renal-pulmonary presentation.1 |
| Multiple sclerosis | CSF-restricted oligoclonal bands and intrathecal immunoglobulin synthesis assessed with paired CSF and serum | Current diagnostic criteria integrate these findings with the clinical and imaging pattern.8 |
| Autoimmune adrenal disease | Anti-21-hydroxylase antibody | The antibody supports an autoimmune cause of primary adrenal insufficiency.1 |
| Poststreptococcal immune disease | Antistreptolysin O and anti-DNase B support recent streptococcal exposure; C3 commonly falls in poststreptococcal glomerulonephritis | Serology is interpreted with timing and the clinical criteria for rheumatic fever or glomerulonephritis.1 |
Red-cell autoantibodies, direct antiglobulin testing, and immune hemolysis are covered in Immune Hemolytic Anemia: Diagnostic Framework and Cold-Reactive Disorders and Warm, Mixed, and Drug-Induced Immune Hemolytic Anemia.
Hypersensitivity mechanisms
The Gell and Coombs scheme groups hypersensitivity reactions by their principal effector mechanism. Many diseases involve overlapping pathways, but the categories identify the predominant mechanism. 1,9
| Type | Principal mediator or effector | Main mechanism | Common timing and examples |
|---|---|---|---|
| I, immediate | Allergen-specific IgE, mast cells, and basophils | Allergen cross-links Fc-epsilon-RI-bound IgE, releasing preformed granule contents, lipid mediators, and newly produced cytokines | Minutes, with a later inflammatory phase; anaphylaxis, allergic rhinitis, food allergy, and some asthma or urticaria |
| II, antibody-mediated | IgG or IgM against a cell, matrix antigen, or receptor | Opsonization, phagocytosis, complement injury, antibody-dependent cellular cytotoxicity, receptor blockade, or receptor stimulation | Hours to days; immune cytopenias, anti-GBM disease, myasthenia gravis, and Graves disease |
| III, immune-complex-mediated | Soluble antigen-antibody complexes | Complex deposition activates complement and recruits inflammatory cells | Hours to days; serum sickness, selected SLE manifestations, and an immune-complex component of hypersensitivity pneumonitis |
| IV, cell-mediated | Sensitized T cells and recruited macrophages | Cytokine-driven inflammation or cytotoxic T-cell injury | Begins in about 24 to 48 hours and commonly peaks at 48 to 72 hours; contact dermatitis, tuberculin-type reactions, and a cellular component of hypersensitivity pneumonitis |
Type I laboratory findings
Sensitization begins when interleukin 4 and interleukin 13 support class switching to allergen-specific IgE. IgE binds high-affinity Fc-epsilon-RI on mast cells and basophils. Later allergen exposure can cross-link those receptors and release histamine, tryptase, proteases, and other preformed mediators. Prostaglandins and leukotrienes arise from membrane lipids, while cytokines require new synthesis and help sustain the later inflammatory phase.
Skin testing and serum allergen-specific IgE are complementary, history-guided approaches. A positive result demonstrates sensitization. Interpretation depends on the exposure and reaction history. Total IgE has poor specificity for an individual allergy.
During suspected anaphylaxis, the 2023 practice parameter recommends collecting an acute serum tryptase as early as practical, ideally within 2 hours after symptoms begin, and a later baseline sample when the patient is well. One established criterion for mast-cell activation is an acute result greater than the baseline multiplied by 1.2, plus 2 ng/mL. Serum tryptase remains within the reference interval in many anaphylactic episodes, especially food-associated reactions, so diagnosis still depends on the clinical presentation.9
Types II, III, and IV in laboratory interpretation
Type II reactions include three related patterns: antibody-mediated clearance of an antigen-bearing cell, receptor blockade, and receptor stimulation. Complement participates in many cytotoxic reactions but contributes less to receptor blockade or stimulation. Some transfusion reactions, hemolytic disease of the fetus and newborn, and autoimmune hemolytic anemia are Blood Banking examples of this mechanism.
Type III injury develops when soluble immune complexes persist and deposit in tissue. Complement activation recruits neutrophils and can lower measured C3 or C4. Complement concentration remains a nonspecific finding and is interpreted with the disease pattern, renal findings, antibody results, and change from the patient’s baseline.
Type IV reactions depend on sensitized T cells. Antigen-specific cytokines recruit and activate macrophages, while cytotoxic T cells can injure target cells directly. Induration in a validated delayed-type skin test is commonly read at 48 to 72 hours. Cellular immunity can also be evaluated with lymphocyte proliferation or activation assays selected for the clinical question.
Monoclonal gammopathy and lymphoid proliferation
A normal immune response commonly produces a broad polyclonal immunoglobulin pattern from many B-cell clones. A monoclonal protein is produced by one restricted B-cell or plasma-cell clone. Clonality establishes the origin of the protein. Disease classification also integrates the amount and type of protein, marrow findings, organ injury, imaging, and the clinical setting.
Serum protein electrophoresis (SPEP) can show a narrow M-protein peak. Serum free-light-chain testing improves detection of light-chain secretion, and serum immunofixation or an equivalent method types a suspicious protein. Current College of American Pathologists guidance recommends SPEP with serum free light chains for the initial evaluation of a suspected monoclonal gammopathy, followed by serum immunofixation when either screen is suspicious.10
Free-light-chain concentrations and ratios depend on renal function, assay design, and the performing laboratory’s reference interval. Selected presentations, including suspected AL amyloidosis, also require urine immunofixation. Chemistry laboratory methods cover detailed interpretation of electrophoresis and free-light-chain testing.
MGUS, smoldering myeloma, and multiple myeloma
The International Myeloma Working Group separates these plasma-cell disorders by monoclonal protein, clonal marrow plasma cells, and myeloma-defining events.11
| Category | Core laboratory and marrow pattern |
|---|---|
| Non-IgM monoclonal gammopathy of undetermined significance (MGUS) | Serum M protein below 3 g/dL, clonal marrow plasma cells below 10%, and no myeloma-defining event, attributable organ injury, or amyloidosis |
| Smoldering multiple myeloma | Serum M protein at least 3 g/dL or urine monoclonal protein at least 500 mg per 24 hours, and/or clonal marrow plasma cells from 10% to below 60%, with no myeloma-defining event or amyloidosis |
| Multiple myeloma | Clonal marrow plasma cells at least 10% or a biopsy-proven plasmacytoma, plus at least one myeloma-defining event |
Attributable CRAB organ injury refers to hypercalcemia, renal impairment, anemia, and bone lesions. It includes calcium more than 1 mg/dL above the upper reference limit or above 11 mg/dL; creatinine clearance below 40 mL/min or serum creatinine above 2 mg/dL; hemoglobin below 10 g/dL or more than 2 g/dL below the lower reference limit; or one or more osteolytic bone lesions. Biomarker-defined events include clonal marrow plasma cells at least 60%; an involved to uninvolved serum free-light-chain ratio at least 100 with the involved light chain at least 100 mg/L; or more than one MRI focal lesion measuring at least 5 mm. Each CRAB finding must be attributable to the plasma-cell disorder.11
Multiple myeloma can secrete intact IgG or IgA, free light chains, another monoclonal protein, or an amount below routine detection. Urinary monoclonal free light chains are called Bence Jones protein. CBC, calcium, creatinine, protein studies, marrow examination, and imaging provide different parts of the classification.11
Waldenström macroglobulinemia requires a monoclonal IgM protein and bone-marrow morphologic evidence of lymphoplasmacytic lymphoma. No minimum IgM concentration or marrow percentage applies. Symptoms distinguish symptomatic from asymptomatic disease. Immunophenotypic and molecular studies help characterize the clone and distinguish IgM MGUS and other B-cell neoplasms. The IgM can produce hyperviscosity, cryoglobulinemia, cold-agglutinin activity, neuropathy, or other protein-mediated findings.12
Detailed leukemia, lymphoma, plasma-cell morphology, immunophenotyping, and molecular classification are covered in Hematology.
Inborn and secondary immunodeficiency
An inborn error of immunity (IEI) results from an inherited or newly arising genetic change that impairs or dysregulates immune function. A secondary immunodeficiency develops from another condition or exposure, such as HIV, hematologic malignancy, protein loss, severe undernutrition, or an immune-modifying medication. Secondary causes are common and must be assessed before attributing a laboratory abnormality to an IEI.13
Clinical patterns guide the first laboratory tests. Age, organism, infection site, severity, frequency, vaccine history, medication exposure, and family history refine the interpretation. 13
| Suspected compartment | Common clues | Initial laboratory direction |
|---|---|---|
| Humoral immunity | Recurrent sinopulmonary bacterial infection, enteroviral disease, or giardiasis | CBC with differential; IgG, IgA, and IgM; age-appropriate antigen-specific antibody responses; B-cell enumeration |
| T-cell or combined immunity | Viral, fungal, opportunistic, or disseminated infection; persistent candidiasis; severe infection in infancy | Absolute lymphocyte count; T-, B-, and NK-cell enumeration; naïve and memory T-cell phenotype; selected proliferation testing |
| Phagocyte number or function | Deep bacterial or fungal infection, poor wound healing, absent pus, or marked neutrophilia | Absolute neutrophil count and morphology; dihydrorhodamine oxidative-burst testing; adhesion markers when indicated |
| Complement | Encapsulated bacterial infection, invasive Neisseria, or lupus-like immune-complex disease | CH50 and AH50 together, followed by implicated components and careful specimen review |
Antigen-Antibody Interactions and Complement explains CH50, AH50, component patterns, and preanalytic loss of complement activity.
Characteristic IEI patterns
These representative patterns guide targeted follow-up; they do not replace confirmatory immune, molecular, or genetic testing.13
| Disorder | Immune defect | Characteristic laboratory clue |
|---|---|---|
| X-linked agammaglobulinemia | BTK-associated arrest before mature B-cell development | Very low or undetectable B cells and immunoglobulins with preserved T-cell numbers; hypomorphic variants can retain some B cells or immunoglobulin |
| Selective IgA deficiency | Predominant loss of serum IgA after age 4 years | Profoundly low or undetectable IgA with normal IgG and IgM; IgA-based serology can give false-negative results |
| Common variable immunodeficiency | Impaired antibody production with heterogeneous B- and T-cell abnormalities | Low IgG with low IgA and/or IgM, impaired antigen-specific antibody response, and exclusion of secondary causes |
| Severe combined immunodeficiency (SCID) | Profound T-cell failure with ineffective humoral immunity | Markedly low T cells and poor function; T, B, and NK enumeration creates genotype-guiding patterns such as T-negative, B-positive, NK-negative; T-negative, B-negative, NK-negative; or T-negative, B-negative, NK-positive |
| Wiskott-Aldrich syndrome | Cytoskeletal defect affecting immune cells and platelets | Thrombocytopenia with small platelets, eczema, and variable immunoglobulin and antibody abnormalities |
| 22q11.2 deletion with thymic hypoplasia | Variable thymic development | Reduced T cells in partial disease and profound T-cell deficiency with complete athymia; molecular testing establishes the deletion |
| Ataxia-telangiectasia | DNA-repair defect with variable combined immune dysfunction | Elevated alpha-fetoprotein is a useful clue; immunoglobulin and lymphocyte abnormalities vary |
| Chronic granulomatous disease | Impaired phagocyte NADPH oxidase activity | Dihydrorhodamine testing shows absent, reduced, or mosaic oxidative burst and guides confirmatory genetic testing |
| Leukocyte adhesion deficiency type I | Reduced or absent CD18-containing integrins | Persistent neutrophilia with reduced CD18 expression, impaired tissue migration, delayed umbilical separation, and poor pus formation |
SCID newborn screening
Newborn screening for SCID measures T-cell receptor excision circles (TRECs) by quantitative PCR in a dried blood spot. TRECs are DNA byproducts of T-cell receptor rearrangement and reflect new T-cell production. A low result signals the need for urgent diagnostic follow-up. SCID diagnosis uses confirmatory immune and genetic findings. Prematurity, complete athymia, 22q11.2 deletion, secondary lymphopenia, and other syndromic disorders can also produce low TRECs. TREC screening primarily detects reduced thymic output and can miss immune defects with preserved T-cell numbers. 13,14
Follow-up commonly includes CBC and absolute lymphocyte count, T-, B-, and NK-cell enumeration, naïve T-cell assessment, functional testing, evaluation for maternal-cell engraftment when appropriate, and directed genetic testing. HIV causes secondary immunodeficiency through progressive CD4 T-cell loss, which increases susceptibility to opportunistic infection. HIV testing uses its own antigen, antibody, nucleic-acid, CD4, and viral-load methods in the infectious-serology sequence. 1
References
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- Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol. 2019;71(9):1400-1412. doi:10.1002/art.40930.
- Barbhaiya M, Zuily S, Naden R, et al. The 2023 ACR/EULAR antiphospholipid syndrome classification criteria. Arthritis Rheumatol. 2023;75(10):1687-1702. doi:10.1002/art.42624.
- Bossuyt X, Cohen Tervaert JW, Arimura Y, et al. Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis. Nat Rev Rheumatol. 2017;13(11):683-692. doi:10.1038/nrrheum.2017.140.
- Hellmich B, Sanchez-Alamo B, Schirmer JH, et al. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis. 2024;83(1):30-47. doi:10.1136/ard-2022-223764.
- American Diabetes Association Professional Practice Committee. 2. Diagnosis and classification of diabetes: Standards of Care in Diabetes-2026. Diabetes Care. 2026;49(suppl 1). doi:10.2337/dc26-S002.
- Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. American College of Gastroenterology guidelines update: diagnosis and management of celiac disease. Am J Gastroenterol. 2023;118(1):59-76. doi:10.14309/ajg.0000000000002075.
- Montalban X, Gold R, Thompson AJ, et al. Diagnosis of multiple sclerosis: 2024 revisions of the McDonald criteria. Lancet Neurol. 2025;24(10):850-865. doi:10.1016/S1474-4422(25)00270-4.
- Golden DBK, Wang J, Waserman S, et al. Anaphylaxis: a 2023 practice parameter update. Ann Allergy Asthma Immunol. 2024;132(2):124-176. doi:10.1016/j.anai.2023.09.015.
- Keren DF, Bocsi G, Billman BL, et al. Laboratory detection and initial diagnosis of monoclonal gammopathies. Arch Pathol Lab Med. 2022;146(5):575-590. doi:10.5858/arpa.2020-0794-CP.
- Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-e548. doi:10.1016/S1470-2045(14)70442-5.
- Treon SP, Tedeschi A, San-Miguel J, et al. Report of consensus Panel 4 from the 11th International Workshop on Waldenstrom macroglobulinemia on diagnostic and response criteria. Semin Hematol. 2023;60(2):97-106. doi:10.1053/j.seminhematol.2023.03.009.
- Orange JS, Chinen J, Horner CC, et al. 2025 inborn errors of immunity practice parameter: guidance from the Joint Task Force on Practice Parameters, the American Academy of Allergy, Asthma & Immunology, the American College of Allergy, Asthma and Immunology, and the Clinical Immunology Society. Ann Allergy Asthma Immunol. 2026;136(4):426-493.e1. doi:10.1016/j.anai.2025.10.026.
- Health Resources and Services Administration. T-cell related lymphocyte deficiencies. Newborn Screening Information Center. Accessed August 29, 2026.