Cell-mediated immunity is accomplished by T lymphocytes (T cells) and their effector response and interactions with other immune cells. T-cell immunodeficiency diseases include severe combined immunodeficiencies (SCIDs), Wiskott-Aldrich syndrome, ataxia telangiectasia, DiGeorge syndrome (22q11.2 deletion syndrome), immuno-osseous dysplasias, dyskeratosis congenita, and chronic mucocutaneous candidiasis.
Quick Answers for Clinicians
Diagnosis
Indications for Testing
Recurrent infections, particularly with opportunistic organisms
Criteria for Diagnosis
Typical SCID | Leaky SCID | Omenn Syndrome | Reticular Dysgenesis |
---|---|---|---|
Absence of or very low CD3 T-cell number (<300/µL), and no or very low T-cell function (<10% LLN), based on PHA response, OR |
Reduced CD3 T-cell number |
Skin rash, generalized |
Absence of T cells or very low T-cell number (<300/µL) |
Presence of maternal-origin T cells |
No maternal engraftment |
No maternal engraftment |
No or very low T-cell function (<10% LLN), based on PHA response |
<30% of LLN T-cell function, based on PHA response
|
CD3 cells detectable at level of ≥300/µL |
Severe neutropenia (ANC <200/µL) |
|
Absent/low T-cell proliferation (≤30% of normal) to antigens to which patient has been exposed |
Sensorineural deafness and/or no granulopoiesis found in bone marrow exam and/or deleterious AK2 mutation |
||
ANC, absolute neutrophil count; LLN, lower level of normal; PHA, phytohemagglutinin Source: Adapted from Shearer, PIDTC, 2014 |
Laboratory Testing
- Initial testing
- HIV testing
- Infants ≤15 months – quantitative nucleic acid amplification test (NAAT)
- Adults – screen for antibodies; confirm positive results with Western blot
- CBC with differential – profound thrombocytopenia with small, nonfunctioning platelets suggests Wiskott-Aldrich syndrome
- Immunoglobulin (quantitative) – if low, proceed with B-cell immunodeficiency testing
- Sweat chloride – if positive, proceed with cystic fibrosis genetic testing
- T-cell immunodeficiency profile testing
- T-cell testing at minimum should include CD4, CD45RA, CD45RO, CD8, CD4:8 ratio, CD3, CD19, and natural killer (NK) cells
- If abnormal, proceed with lymphocyte antigen- and mitogen-induced lymphocyte proliferation testing
- Consider anti-CD3/anti-CD28/IL-2-induced lymphocyte proliferation test
- HIV testing
- Cell-mediated immune screen
- Lymphocyte antigen and mitogen proliferation test
- Measures tritiated thymidine (3H-TdR) uptake by lymphocytes in response to stimulus (requires 5-7 days)
- Low with low T cells confirms T-cell disorder
- Lymphocyte antigen and mitogen stimulation with cytokines
- Lymphocyte antigen and mitogen proliferation test
- Further specific genetic testing based on results of above testing
Differential Diagnosis
- HIV
- Immunoglobulin disorders
- Complement deficiencies
- Chronic granulomatous disease (CGD)
- Neutrophil disorders
Background
Epidemiology
- Incidence – rare
- Age – most commonly discovered during neonatal period and infancy
- Adult onset rare
- Sex – M:F, equal, except for X-linked diseases
- M>F for X-linked severe combined immunodeficiencies (SCIDs) and Wiskott-Aldrich syndrome
Inheritance
For inheritance, refer to Identified Forms of SCID tables
Pathophysiology
- Defective lymphocyte responses to stimulants may occur
- Nonspecific mitogens (phytohemagglutinin, concanavalin A, and pokeweed mitogen)
- Specific antigens, such as Candida or tetanus
- Characterized by increased susceptibility to infections from opportunistic organisms
- Cytomegalovirus (CMV)
- Candida albicans
- Pneumocystis jirovecii
Clinical Presentation
- Clinical presentation is highly variable but can be divided into 2 main types
- Immunodeficiencies with associated or syndromic features (including both immune and nonimmune manifestations, as in Wiskott-Aldrich syndrome and DiGeorge syndrome [22q11.2 deletion syndrome])
- Ataxia telangiectasia (European Society for Immunodeficiencies [ESID])
- Progressive cerebellar ataxia
- Ocular or facial telangiectasia
- Recurrent respiratory infections
- Difficulty walking; wheelchair bound by teenage years
- Increased risk of malignancy – leukemia/lymphoma in 10-15% of patients
- DiGeorge syndrome (22q11.2 deletion syndrome) (ESID)
- Cardiac defect – may be conotruncal
- Persistent infections (fungal or viral)
- Hypocalcemia, hypocalcemic tetany (due to hypoparathyroidism)
- Abnormal facies
- Palatal abnormalities
- Autoimmune disorders
- Wiskott-Aldrich syndrome – in males (ESID)
- Congenital thrombocytopenia with small platelets
- Bloody diarrhea
- Otitis, sinusitis
- Recurrent infections (bacterial or viral)
- Eczema
- Commonly, associated autoimmune disease
- Increased risk for malignancy
- Ataxia telangiectasia (European Society for Immunodeficiencies [ESID])
- Immunodeficiencies without associated or syndromic features
- Omenn syndrome (Genetic and Rare Diseases Information Center)
- Erythroderma and desquamation; alopecia
- Chronic diarrhea
- Failure to thrive
- Lymphadenopathy
- Eosinophilia
- Hepatosplenomegaly
- High susceptibility to infection (viral, fungal, bacterial)
- SCID – often in first 2-7 months of life (ESID)
- Failure to thrive
- Persistent diarrhea
- Respiratory symptoms and/or thrush
- Pneumocystis pneumonia
- Disseminated bacillus Calmette-Guérin infection
- Refer to Identified Forms of SCID table
- Leaky SCID (National Organization for Rare Diseases)
- Severe itchy rashes
- Enlarged lymph nodes, spleen, and liver
- Chronic diarrhea
- Omenn syndrome (Genetic and Rare Diseases Information Center)
- Immunodeficiencies with associated or syndromic features (including both immune and nonimmune manifestations, as in Wiskott-Aldrich syndrome and DiGeorge syndrome [22q11.2 deletion syndrome])
Identified Forms of SCID
Gene | T Cells | B Cells | NK Cells | Genetics | Associated Features |
---|---|---|---|---|---|
T-negative/B-positive SCID | |||||
IL2RG |
Very low |
Normal to high |
Low |
XL |
Impaired cytokine-mediated signaling |
JAK3 |
Very low |
Normal to high |
Low |
AR |
Impaired cytokine-mediated signaling |
IL7R |
Very low |
Normal to high |
Normal |
AR |
Impaired cytokine-mediated signaling |
PTPRC |
Very low |
Normal |
n/a |
AR |
— |
CD3D |
Very low |
Normal |
Normal |
AR |
CD3-delta deficiency |
CD3E |
Very low |
Normal |
Normal |
AR |
CD3-epsilon deficiency |
CD247 |
Very low |
Normal |
Normal |
AR |
— |
CORO1A |
Very low |
Normal |
n/a |
AR |
Detectable thymus, EBV |
LAT |
Normal to low number |
Normal to low |
n/a |
AR |
Adenopathy, splenomegaly, recurrent infections, autoimmunity |
T-negative/B-negative SCID | |||||
RAG1b |
Very low |
Very low |
Normal |
AR |
Associated with Omenn syndrome |
RAG2b |
Very low |
Very low |
Normal |
AR |
Associated with Omenn syndrome |
DCLRE1C |
Very low |
Very low |
Normal |
AR |
Radiation sensitivity; Omenn syndrome |
PRKDC |
Very low |
Very low |
Normal |
AR |
Radiation sensitivity; microcephaly |
NHEJ1 |
Very low |
Very low |
Normal |
AR |
Radiation sensitivity; microcephaly |
LIG4 |
Very low |
Very low |
Normal |
AR |
Radiation sensitivity; microcephaly |
AK2 |
Very low |
Normal to low |
n/a |
AR |
Granulocytopenia and deafness; reticular dysgenesis |
ADAb |
Very low |
Low, decreasing |
Low |
AR |
Bone defects; may have pulmonary alveolar proteinosis; cognitive defects |
aSources in addition to the International Union of Immunological Societies Primary Immunodeficiency Diseases Committee report (Picard, 2018) include Cossu (2010) and van der Burg (2011) bGene included on Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication – ARUP test code 2011156 ADA, adenosine deaminase; AR, autosomal recessive; EBV, Epstein-Barr virus; n/a, not applicable; NK, natural killer; XL, X-linked |
Gene | T Cells | B Cells | Genetics | Comment |
---|---|---|---|---|
DOCK2 |
Low |
Normal |
AR |
Impaired interferon response in hematopoietic and nonhematopoietic cells; normal NK numbers but defective function |
CD40LGb |
Normal to low |
sIgM+ and sIgD+ B cells present, other surface isotype positive B cells absent |
XL |
Neutropenia; thrombocytopenia; hemolytic anemia; liver/biliary tract disease; opportunistic infections |
CD40b |
Normal |
IgM+ and IgD+ cells present, other isotypes absent |
AR |
Neutropenia; GI and liver/biliary tract disease; opportunistic infections |
ICOSb |
Normal |
Normal |
AR |
Recurrent infections; autoimmunity; gastroenteritis; granulomas in some cases |
PNP |
Progressive decrease |
Normal |
AR |
Autoimmune hemolytic anemia; neurological impairment |
CD3G |
Normal number; low TCR expression |
Normal |
AR |
— |
CD8A |
Absent CD8, normal CD4 cells |
Normal |
AR |
Recurrent infections; may be asymptomatic |
ZAP70 |
Low CD8, normal CD4 cells |
Normal |
AR |
In some cases, immune dysregulation, autoimmunity |
TAP1, TAP2, or TAPBP |
Low CD8, normal CD4 cells |
Normal |
AR |
Vasculitis; pyoderma gangrenosum |
B2M |
— |
Normal |
AR |
— |
CIITA, RFXANK, RFX5, RFXAP |
Low CD4 cells |
Normal |
AR |
Respiratory and GI infections; liver/biliary tract disease |
ITK |
Progressive decrease |
Normal |
AR |
EBV-associated B-cell lymphoproliferation, lymphoma; normal or low IgG |
MAGT1 |
Low CD4 cells |
Normal |
XL |
EBV infection; lymphoma; viral infections; respiratory and GI infections |
DOCK8 |
Low |
Low; low CD27+ memory B cells |
AR |
Eosinophilia; recurrent infections; severe atopy; cutaneous viral, staphylococcal, and fungal infections; cancer susceptibility; low/impaired function NK cells |
RHOH |
Normal number |
Normal |
AR |
HPV infection; lymphoma; lung granulomas; molluscum contagiosum |
SH2D1Ab |
Normal or increased activated T cells |
Reduced memory B cells |
XL |
Clinical and immunologic features induced by EBV infection; HLH; lymphoproliferation; aplastic anemia; lymphoma; hypogammaglobulinemia |
RMRP |
Varies from severely low to normal; impaired lymphocyte proliferation |
Normal |
AR |
Short-limbed dwarfism with metaphyseal dysostosis; sparse hair; bone marrow failure; autoimmunity; cancer/lymphoma susceptibility; impaired spermatogenesis; neuronal dysplasia of the intestine |
STK4 |
Low |
Low |
AR |
Recurrent bacterial, viral/HPV, and candidal infections; intermittent neutropenia; EBV lymphoproliferation; lymphoma; congenital heart disease; autoimmune cytopenias |
TRAC |
Absent TCR alpha beta cells |
Normal |
AR |
Recurrent viral, bacterial, and fungal infections; immune dysregulation autoimmunity; diarrhea |
LCK |
Low CD4+ and T regulatory cells |
Normal |
AR |
Recurrent infections; immune dysregulation; autoimmunity |
MALT1b |
Normal number |
Normal |
AR |
Bacterial, fungal, and viral infections |
CARD11b |
Normal number |
Normal predominance of transitional B cells |
AD, AR |
Pneumocystis jirovecii pneumonia, bacterial and viral infections |
BCL10 |
Normal number |
Normal number |
AR |
Recurrent bacterial and viral infections; candidiasis; gastroenteritis |
BCL11B |
Low |
Normal |
AD |
Congenital abnormalities, neonatal teeth, facies abnormalities, absent corpus callosum, neurocognitive defects |
IL21b |
Normal number |
Low |
AR |
Severe onset early colitis; sinopulmonary infections |
IL21Rb |
Normal number |
Normal number |
AD, AR |
Recurrent infections; susceptibility to cryptosporidium and pneumocystis infections and liver disease |
TNFRSF4 |
Normal number |
Normal number |
AR |
Kaposi sarcoma; impaired immunity to HHV8 |
IKBKB |
Normal number |
Normal number |
AR |
Recurrent bacterial, viral, and fungal infections; opportunistic infections |
PIK3CDb |
— |
Low or absent pro-B cells |
AD |
Severe bacterial infections; EBV |
LRBAb |
Normal/decreased CD4 number |
Low or normal number |
AR |
Recurrent infections; IBD; autoimmunity; EBV infection |
CD27b |
Normal |
No memory B cells |
AR |
Clinical and immunologic features triggered by EBV infection; HLH; aplastic anemia; lymphoma; hypogammaglobulinemia; low iNKT cells |
RELB |
Normal number |
— |
AR |
Recurrent infections |
MSN |
Normal number |
Low number |
XL |
Recurrent infections with bacteria, varicella, neutropenia |
TFRC |
Normal number |
Normal number, low memory B cells |
AR |
Recurrent infections, neutropenia, thrombocytopenia |
MAP3K14b |
Normal number |
Low |
AR |
Recurrent bacterial, viral, and Cryptosporidium infections; low NK cell number |
CTPS1 |
Normal or decreased |
Normal or decreased |
AR |
Recurrent/chronic viral infections (particularly EBV, VZV), lymphoproliferation; B-cell NHL |
aBased on the International Union of Immunological Societies Primary Immunodeficiency Diseases Committee report (Picard, 2018); see original source for additional detail about T-cell and B-cell status and function bGene included on Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication – ARUP test code 2011156 AD, autosomal dominant; AR, autosomal recessive; CMV, cytomegalovirus; EBV, Epstein-Barr virus; GI, gastrointestinal; HHV8, human herpesvirus 8; HLH, hemophagocytic lymphohistiocytoses; HPV, human papillomavirus; IBD, irritable bowel disease; iNK, invariant natural killer; NHL, non-Hodgkin lymphoma; NK, natural killer; TEMRA, terminal differentiated effector memory cells; Treg, regulatory T cells; VZV, varicella-zoster virus; XL, X-linked |
ARUP Laboratory Tests
Detect HIV-1 RNA
Qualitative Transcription Mediated Amplification
Detect and quantify HIV-1
"Not Detected" result does not rule out the presence of inhibitors or HIV-1 virus RNA concentrations below the assay detection level
Quantitative Transcription-Mediated Amplification
Screen for HIV-1,2 antibodies and antigens
Qualitative Chemiluminescent Immunoassay /Qualitative Western Blot
Assess for thrombocytopenia
Automated Cell Count/Differential
Initial test in the workup of immunoglobulin disorders
In adults and older children with suspected hypogammaglobulinemia, order in conjunction with serum protein electrophoresis and immunofixation
Quantitative Immunoturbidimetry
Assess thymic function in suspected severe combined immunodeficiency (SCID), DiGeorge syndrome (22q11.2 deletion syndrome), and other T-cell immune deficiency disorders
Evaluate immune reconstitution during highly active antiviral therapy (HAART) in HIV patients and post chemotherapy and hematopoietic cell transplant
Quantitative Flow Cytometry
Useful for assessing primary T-cell immunodeficiency disorders
Test enumerates the percent and absolute cell count of lymphocyte subsets in whole blood for CD3 (total T cells), CD4 (helper T cells), CD45RA (naive helper T cells), CD45RO (memory helper T cells), CD8 (cytotoxic T cells), CD4:CD8 ratio, CD19 (B cells), natural killer (NK) cells
Quantitative Flow Cytometry
Acceptable lymphocyte subset panel for the investigation of primary immunodeficiency disorders
Test enumerates the percent and absolute cell count of lymphocyte subsets in whole blood for CD2, CD3 (total T cells), human leukocyte antigen-antigen D related (HLA-DR), CD4 (helper T cells), CD45RA (naive helper T cells), CD45RO (memory helper T cells), CD8 (cytotoxic T cells), CD4:CD8 ratio, CD19 (B cells), NK cells
Quantitative Flow Cytometry
Evaluate NK- and NKT-cell subsets
Semi-Quantitative Flow Cytometry
Panel includes:
- Pct CD3-CD16-/+CD56br/dim (total NK cells)
- Abs CD3-CD16-/+CD56br/dim (total NK cells)
- Pct CD3-CD16+CD56dim (cytotoxic NK cells)
- Abs CD3-CD16+CD56dim (cytotoxic NK cells)
- Pct CD3-CD16-CD56br (cyto secreting NK)
- Abs CD3-CD16-CD56br (cyto secreting NK)
- Pct CD3-CD57+ (CD57 NK cells)
- Abs CD3-CD57+ (CD57 NK cells)
- Pct CD3+CD56+ (CD56 NKT cells)
- Abs CD3+CD56+ (CD56 NKT cells)
- Pct CD3+CD57+ (CD57 NKT cells)
- Abs CD3+CD57+ (CD57 NKT cells)
- Pct CD45+CD3+ (T cells)
- Abs CD45+CD3+ (T cells)
- Pct CD45+CD3- (non T cells)
- Abs CD45+CD3- (non T cells)
- Natural killer T-cell panel interpretation
Evaluate NK cells in patients with suspected immune deficiency
Quantitative Flow Cytometry
Primarily for evaluating lymphocyte function in patients with suspected cellular immune dysfunction, such as primary and secondary immunodeficiencies
Other uses include monitoring lymphocyte recovery and competence after hematopoietic stem cell transplantation and monitoring lymphocyte function during immunosuppressive therapy
Cell Culture/Flow Cytometry
Primarily for research and to support attempts to understand the pathogenesis of immune, infectious, allergic, or inflammatory disorders
Test for lymphocyte proliferation in response to:
Phytohemagglutinin
Concanavalin A
Pokeweed mitogen
Candida antigen
Tetanus antigen
Cell Culture
Primarily for evaluating T-cell function in patients with suspected cellular immune dysfunction, such as primary and secondary immunodeficiencies
Other uses include monitoring lymphocyte recovery and competence after hematopoietic stem cell transplantation and monitoring lymphocyte function during immunosuppressive therapy
Not a first-level test; order after lymphocyte proliferation, mitogen induced, by flow cytometry has been performed
Cell Culture/Flow Cytometry
Primarily for evaluating recall antigen responses in patients with suspected cellular immune dysfunction, such as primary and secondary immunodeficiencies
Other uses include monitoring lymphocyte recovery and competence after hematopoietic stem cell transplantation and monitoring lymphocyte function during immunosuppressive therapy
Do not order for patients younger than 3 months unless clinical history of candidiasis is present
Cell Culture/Flow Cytometry
Primarily for evaluating lymphocyte function in patients with suspected cellular immune dysfunction, such as primary and secondary immunodeficiencies
Other uses include monitoring lymphocyte recovery and competence after hematopoietic stem cell transplantation and monitoring lymphocyte function during immunosuppressive therapy
Cell Culture/Flow Cytometry
Rapid test for Candida and tetanus antigens
Use to evaluate chronic infections
Cell Culture
Medical Experts
Delgado

Hillyard

Lamb

Slev

Wittwer

References
GeneReviews WAS-Related Disorders - Tcell
Chandra S, Bronicki L, Nagaraj CB, et al. WAS-Related Disorders. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Sep 2016; Accessed: Feb 2020]
ESID - Clinical: Diagnostic criteria for PID
Clinical: Diagnostic criteria for PID. European Society for Immunodeficiencies (ESID).[ Accessed: Jan 2018]
21078154
GeneReviews Ataxia-Telangiectasia - Tcell
Gatti R, Perlman S. Ataxia-telangiectasia. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Oct 2016; Accessed: Feb 2020]
GeneReviews Adenosine Deaminase Deficiency - Tcell
Hershfield M. Adenosine Deaminase Deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Mar 2017; Accessed: Feb 2020]
IDF - Tcell Deficiency Disorders
11224843
NCATS - Omenn Syndrome
29226302
Picard C, Gaspar B, Al-Herz W, et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee report on inborn errors of immunity. J Clin Immunol. 2018;38(1):96-128.
NORD - Severe Combined Immunodeficiency
National Organization for Rare Disorders. Rare Disease Database: severe combined immunodeficiency. National Organization for Rare Disorders (NORD).[ Accessed: Jan 2018]
Reflex pattern: if HIV-1,2 combo antigen/antibodies screen is repeatedly reactive, then HIV-1 antibody confirmation by Western Blot will be added