CD Markers CD1 to CD49
Last revised 2 March 2008
Copyright © 2001-2008 PathologyOutlines.com, Inc.
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Primary references
American Journal of Clinical Pathology (AJCP), August 1975 to February 2006
American Journal of Surgical Pathology (AJSP), March 1977 to February 2006
Archives of Pathology and Lab Medicine (Archives), January 1976 to February 2006
Human Pathology (Hum Path), March 1970 to February 2006
Modern Pathology (Mod Path), January 1988 to February 2006
Rosai, J: Ackerman’s Surgical Pathology (9th Ed); Mosby, 2004
Sternberg,
S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins,
2004
University
of Pittsburgh Medical Center Case Reports, cases 1-462
CD Marker websites: http://ca.expasy.org/cgi-bin/lists?cdlist.txt, Protein Reviews On the Web, http://www.ebioscience.com/ebioscience/whatsnew/humancdchart.htm
Background
CD: cluster designation or cluster of differentiation
Nomenclature proposed in 1982 at First International Workshop and Conference on Human Leukocyte Differentiation Antigens (HLDA); workshops now called Human Cell Differentiation Molecules
Classification system for monoclonal antibodies generated by laboratories worldwide against cell surface molecules on leukocytes initially, now also antigens from other cell types
Data collated and analyzed by cluster analysis based on pattern of binding to leukocytes or other cell types
Must be at least two monoclonal antibodies for each antigen
“w" indicates the CD is not well characterized or is represented by only one monoclonal antibody
Interpretation should be based on cellular distribution of staining (i.e. membranous, cytoplasmic, nuclear), proportion of positively stained cells, staining intensity and cutoff levels
Used in immunohistochemistry and flow cytometry
References: J Immunol 1994;152:1, Bull World Health Organ 1997;75:385, J Immunol Methods 2003;275:1-8, Blood 2005;106:3123
Family of non-polymorphic MHC class I-like glycoproteins on surface of various antigen-presenting cells
Member of immunoglobulin superfamily
Has 5 different subsets (CD1a - CD1e), all noncovalently associated with beta 2 microglobulin, all on #1q22-23 (non MHC linked)
The different CD1 forms bind to different types of lipid antigen based on differences in their antigen binding grooves (Nat Rev Immunol 2005;5:387)
Cellular infection with live Mycobacteria tuberculosis or exposure to mycobacterial cell wall products converts CD1 negative myeloid precursors into competent CD1+ antigen presenting cells (J Immunol 2005;175:1758); pollen lipids are also recognized as antigens by T cells via CD1 dependent pathway (J Exp Med 2005;202:295); may generate inflammatory component in atherosclerotic lesions (Am J Pathol 1999;155:775)
Inhibition of CD1 expression may be a mechanism of immune system evasion by metastatic melanoma (Am J Path 2004;165:1853), Leishmania donovani (Infect Immun 2004;72:589), and some Mycobacterial infections
Function: involved in presentation of autologous and bacterial lipid antigens to T cells; may also mediate thymic T cell development
Uses: diagnosis of Langerhans cell histiocytosis
Positive staining (normal): cortical thymocytes (70%), activated T cells, Langerhans cells, interdigitating dendritic cells
Positive staining (disease): Langerhans cell histiocytosis, pre T ALL with cortical thymocyte phenotype; indolent T cell lymphoblastic proliferations (AJSP 1999;23:977; AJSP 2001;25:411), thymoma (Jpn J Thorac Cardiovasc Surg 2003;51:481)
Negative staining: mature peripheral T cells, peripheral T cell lymphomas
Also called Leu6
On chromosome 1q22-23 (not MHC linked)
T cell surface antigen important in dendritic cell presentation of glycolipids and lipopeptide antigens
May activate intrathyroidal T cells in Hashimoto’s thyroiditis and Grave’s disease (J Immunol 2005;174:3773)
Interpretation: membranous staining
Uses: diagnosis of Langerhans cell histiocytosis and exclusion of other entities that are CD1a negative
Micro images: Langerhans cell histiocytosis - (1) lung; (2) thyroid; (3) leprosy patient; (4) skin #1; (5) site unknown #1; #2; (6) cytology
other - (7) CD1a+ Langerhans cells in normal skin; (8) CD1a+ cortical thymocytes in normal thymus; (9) psoriasis
Positive staining (normal): cortical thymocytes, Langerhans cells (Langerin+, CD86+), immature dendritic cells (Langerin-, CD86-, HLA-DR low, CD40-low)
Positive staining (disease): Langerhans cell histiocytosis (fairly specific), myeloid leukemias, mycosis fungoides (variable), almost all cutaneous T cell lymphomas, T-ALL (age 28-60 years, AJCP 2002;117:252), dendritic cells in dermis/epidermis of benign inflammatory skin disorders including pseudolymphomatous folliculitis (AJSP 1999;23:1313), spongiotic dermatitis and lichen planus (Arch Dermatol Res 2002;294:297), psoriasis (J Cutan Pathol 1995;22:223); Barrett’s metaplasia of esophagus (Br J Cancer 2005;92:888), monocytes in most sickle cell anemia patients (Hum Immunol 2004;65:1370)
Negative staining: normal B cells, dendritic cells in most cutaneous B cell lymphomas (AJCP 2001;116:72), histiocytic lymphoma / sarcoma, histiocytoma, follicular dendritic cells, follicular dendritic cell tumor, interdigitating dendritic cells (variable, AJSP 1998;22:1048, AJCP 2001;115:589), interdigitating dendritic cell sarcoma, dendritic cell neurofibroma, juvenile xanthogranuloma, sinus histiocytosis with massive lymphadenopathy, Erdheim-Chester disease
References: AJSP 2001;25:630 (Langerhans cell histiocytosis), J Clin Invest 2004;113:701 (Langerhans cells), OMIM 188370
CD1b
On chromosome 1q22-23 (not MHC linked); noncovalently associated with beta2 microglobulin
Can present to antigen presenting cells a set of glycolipid species with broad range of variation in length of acyl chains (J Immunol 2004;172:2382), including those from pathogenic Mycobacteria tuberculosis and Mycobacteria leprae to cytotoxic T cells
Uses: no significant clinical use by pathologists
Micro images: leprosy patient
Positive staining (normal): cortical thymocytes, Langerhans cells (weaker staining than CD1a), myeloid dendritic cells, brain pyramidal cells, subpopulation of B cells
Positive staining (disease): dendritic cells in mycosis fungoides (J Cutan Pathol 1995;22:223); myeloid leukemias, some B and T cell malignancies, monocytes of most sickle cell anemia patients (Hum Immunol 2004;65:1370)
Negative staining: normal B cells
References: OMIM 188360
CD1c
On chromosome 1q22-23 (not MHC linked); noncovalently associated with beta 2 microglobulin
Activated by phospholipid antigen produced by Mycobacteria tuberculosis and M. bovis Bacille-Calmette-Guerin (J Exp Med 2004;200:1559, Nature 2000;404:884); assists with presentation of lipid antigens
May activate intrathyroidal T cells in Hashimoto’s thyroiditis and Grave’s disease (J Immunol 2005;174:3773); may promote autoantibodies in systemic lupus erythematosus (J Immunol 2000;165:5338)
B-CLL cells downregulate CD1c genes, which may mediate evasion of immune response (Leukemia 2002;16:2429)
Uses: no significant clinical use by pathologists
Positive staining (normal): cortical thymocytes, Langerhans cells (weaker than CD1a), immature myeloid dendritic cells, subset of normal peripheral B cells, activated T cells
Positive staining (disease): dendritic cells in mycosis fungoides (J Cutan Pathol 1995;22:223); myeloid leukemias and some B and T cell malignancies, monocytes of most sickle cell anemia patients (Hum Immunol 2004;65:1370)
Negative staining: many normal B cells
References: OMIM 188340
CD1d
On chromosome 1q22-23 (not MHC linked)
NK T cells are defined as CD1d dependent T cells that carry an invariant TCR alpha-chain and produce high levels of cytokines
CD1d is expressed in NK T cells active in autoimmune diabetes, tumor rejection and some microbial infections
May protect against lipid antigen-rich infectious microbes on human scalp (J Clin Pathol 2005;58:1278)
B-CLL cells downregulate CD1d genes, which may mediate evasion of immune response (Leukemia 2002;16:2429)
Uses: no significant clinical use by pathologists
Positive staining (normal): dendritic cells, intestinal epithelial cells, B cell subset, NK T cell subset (Immunol Lett 2005;100:42, J Immunol 2005;175:4416), low levels in thymus and monocytes
Positive staining (disease): some B and T cell malignancies; keratinocytes in psoriasis
References: OMIM 188410
CD1e
On chromosome 1q22-23 (not MHC linked); noncovalently associated with beta 2 microglobulin
Processes mycobacterial antigen (instead of presenting antigen directly), and helps expand repertoire of glycolipid T cell antigens to optimize the immune response (Science 2005;310:1321); presentment is done by CD1b
Uses: no significant clinical use by pathologists
Positive staining (normal): dendritic cells
References: OMIM 188411
Also called E rosette receptor (anti-CD2 antibodies inhibit formation of rosettes with sheep erythrocytes), LFA2 (leukocyte function antigen), T11
At 1p13.1; member of immunoglobulin superfamily
Early T cell marker
Functions: (a) binds CD58 (LFA3) on antigen-presenting cells, which enables T cells to respond to lower concentrations of antigen (J Exp Med 1999;190:1383); (b) induces costimulatory signals in T cells (c) induces T cell cytokine production; (d) mediates adhesion between T cells and antigen presenting cells; (e) regulates T and NK-mediated cytolysis; (f) inhibits apoptosis of activated peripheral T cells; (g) regulates T cell anergy
Uses: T cell marker (although CD3 is more common), marker of systemic mastocytosis
Interpretation: membranous staining
Micro images: T cell lymphoma-site unknown; pyothorax associated lymphoma
Positive staining (normal): thymocytes (95%), mature peripheral T cells (almost all), NK cells (80-90%), thymic B cells (50%)
Positive staining (disease): T-ALL, other T cell lymphoma/leukemia, indolent systemic mastocytosis (Hum Path 2001;32:545), variable acute myeloid lymphoma-M0, rarely pyothorax associated B cell lymphoma (AJSP 2002;26:724, Univ Pittsburgh case report), rarely Reed-Sternberg/Hodgkin’s cells (Mod Path 2005;18:1542), rarely myeloma (Mod Path 1990;3:302), rarely myeloid leukemia
Negative staining: B cells, nonhematopoietic neoplasms (AJCP 2003;120:64), mast cells in non-mastocytosis disorders
CD2R
CD2 epitope present on activated T cells, unmasked by conformational change of CD2 glycoprotein during activation
Uses: no significant clinical use by pathologists
Positive staining (normal): activated T cells
Positive staining (disease): blood and synovial fluid T cells in rheumatoid arthritis; peripheral blood T cells in juvenile rheumatoid arthritis, SLE, ankylosing spondylitis and Lyme disease (Scand J Immunol 1991;34:351)
Also called OKT3
Member of immunoglobulin superfamily on 11q23
Complex of delta, epsilon, gamma, zeta and eta chains of integral membrane glycoproteins that associates with T cell antigen receptor (TCR), and is required for TCR cell surface expression and signal transduction
TCR-CD3 complex consists of either TCR alpha/beta or TCR gamma/delta heterodimers coexpressed at the cell surface with CD3
CD3 delta and epsilon defects cause autosomal recessive severe combined immunodeficiency (no T cells, normal B cells, normal NK cells, OMIM 608971, Curr Opin Allergy Clin Immunol 2004;4:479)
CD3 zeta interacts with HIV Nef protein (J Exp Med 1999;189:1489)
Uses: most specific T cell antibody; diminished expression in T cell cutaneous lymphoma (AJCP 2000;114:467), although another study finds CD8:CD3 ratio <25% in epidermal component of lymphocytic infiltrate in these tumors (Mod Path 2003;16:857); treatment with anti-CD3 antibodies may restore self-tolerance in autoimmune diseases (Curr Opin Immunol 2005;17:632, Ann NY Acad Sci 2004;1037:1)
Interpretation: cytoplasmic expression at early T cell differentiation, then membranous expression
Micro images:
NK/T cell lymphoma: (1) testes-CD3 epsilon+ (figure 3D); (2) head & neck
reactive T cells: (3) acute cellular rejection; (4) autoimmune thyroiditis (figure 3)
Additional images: intraepithelial lymphocytes in duodenum (figure 1b); increased intraepithelial lymphocytes at villous tip (figure 2c)
Virtual slides: diffuse large B cell lymphoma (CD3+ reactive T cells)
Positive staining (normal): thymocytes, peripheral T cells, NK cells (CD3 epsilon, cytoplasmic in 56%, not membranous); also Purkinje cells of cerebellum; note: nonspecific cytoplasmic staining may be present in plasma cells and macrophages
Positive staining (disease): 80% of T cell lymphomas, NK lymphoma (cytoplasmic, not membranous), lymphomatoid granulomatosis, lymphomatoid papulosis; variable in primary effusion lymphoma and pyothorax associated lymphoma
Negative staining: most B cell lymphomas, NK large granular lymphocyte leukemia, Reed-Sternberg cells are negative in Hodgkin’s lymphoma but may be surrounded by CD3 epsilon+ rosettes, small cell carcinoma, melanoma, granulocytic sarcoma, post-transplant lymphoproliferative disorders
References: OMIM 186790 (CD3 delta), OMIM 186830 (CD3 epsilon), OMIM 186740 (CD3 gamma), OMIM 186780 (CD3 zeta); AJCP 2005;124:199 (adult T cell leukemia/lymphoma), AJSP 2001;25:1413 (achalasia in esophagectomy specimens)
Also called OKT4
At #12pter-p12
Nonpolymorphous glycoproteins belonging to immunoglobulin superfamily
Expressed on surface of T helper cells; serves as coreceptor in MHC class II-restricted antigen induced T cell activation
CD4+ CD25+ T cells maintain peripheral tolerance and prevent autoimmunity (Curr Top Microbiol Immunol 2005;293:115)
Serves as HIV receptor on T cells, macrophages, brain
Downregulated by HIV Nef protein during AIDS progression (J Virol 2003;77:11536, J Biol Chem 2003;278:33912)
Normally CD4 > CD8; in HIV patients, CD4/CD8 ratio is inverted (i.e. CD4 < CD8) and patients are at risk for opportunistic infections
Homologous to CD223
Uses: classify lymphomas and inflammatory conditions; serum levels are marker of HIV disease progression and response to therapy (CD4+ cells are killed by HIV); serum levels also increased by transient stress (AJCP 2002;117:819)
Drawings: (1) CD4+ T cell and antigen presenting cell; (2) HIV entry into T cells
Positive staining (normal): thymocytes (80-90%), T helper cells, macrophages, Langerhans cells, dendritic cells, granulocytes
Positive staining (disease): many post-thymic T cell leukemia/lymphomas, indolent T cell lymphoblastic proliferation, pityriasis lichenoides, CD4+ CD56+ hematodermic malignancies (blastic NK lymphoma), histiocytic lymphoma / sarcoma, acute myeloid leukemia (AJCP 1995;104:204), some pyothorax associated lymphomas, cutaneous lymphomatoid granulomatosis (AJSP 2001;25:1111), lymphomatoid papulosis (variable), florid antiviral inflammatory response (Mod Path 2003;16:166)
Negative staining: NK cells, T cell lymphoma with cytotoxic phenotype, hepatosplenic alpha/beta and gamma/delta lymphoma, enteropathy associated T cell lymphoma, B cell lymphoma (usually), Hodgkin’s lymphoma (usually), nonhematopoietic neoplasms
References: Cell 1985;42:93 (early article), OMIM 186940
Belongs to ancient scavenger receptor superfamily; at 11q13
CD5+ B cells, which may arise from B-1 cells (subset of B cells) produce “generalist antibodies” - polyreactive low affinity "natural" antibodies to exogenous antigens (tetanus toxoid, lipopolysaccharide) as well as autoreactive antibodies (Immunol Lett 1993;38:159)
First line of defense against antigens; have a low activation threshold; are the only line of defense for those who cannot produce specific antibody
Produce antibodies using germ line (non mutated) configuration of gene segments, usually IgM
CD5 production is elevated in rheumatoid arthritis (27-52% of circulating B cells vs. 20% normal)
CD5 may serve as a dual receptor, giving either stimulatory or inhibitory signals depending both on the cell type and the development stage
Key regulator of immune tolerance; abnormalities may produce autoimmunity (Immunol Res 2002;26:255)
Binds to CD72
Polymorphism in CD5 promoter associated with susceptibility to mantle cell lymphoma and CLL (AJCP 2005;123:646)
Uses: marker for CLL, mantle cell lymphoma, T cells (normal and malignant), thymic carcinoma
Micro images: (1) mantle cell lymphoma (figure 3D); (2) thymic carcinoma (nonkeratinizing squamous cell subtype); (3) CD5+ T-Cell/histiocyte-rich large B-cell lymphoma (figure 3D)
Flow cytometry images: mantle cell lymphoma #1 with coexpression of CD5 and CD19; #2
Positive staining (normal): thymocytes, almost all T cells, B cells of mantle zone of spleen and lymph nodes (12% of B cells in peripheral blood, AJCP 2004;121:368), B cells in peritoneal and pleural cavities
In fetus, most B cells in spleen and cord blood are CD5 positive
Positive staining (disease): B cell CLL/SLL, mantle cell lymphoma (80-90%), diffuse large B cell lymphoma (10%-usually aggressive), aggressive variant of follicular lymphoma (rare, AJCP 2005;124:182), most T cell malignancies, NK/T cell lymphoma (variable), prolymphocytic leukemia, atypical thymoma (some), thymic carcinoma (almost all), CASTLE (thyroid tumor)
Negative staining: enteropathy associated T cell lymphoma, hepatosplenic alpha-beta and gamma-delta T cell lymphomas, T cell large granular lymphocytic lymphoma, most B cell lymphomas other than mantle cell or CLL (although there rarely are CD5+ variant forms), Reed-Sternberg cells in Hodgkin’s lymphoma
References: OMIM 153340
Belongs to ancient scavenger receptor superfamily; at #11q13
Adhesion molecule mediating the binding of developing thymocytes with thymic epithelial cells
Antibodies to CD6 are used to deplete T cells from bone marrow transplants to prevent graft versus host disease (J Clin Oncol 2001;19:1152, Int J Hematol 1999;69:27)
Binds to CD166 (ALCAM); essential for stable T cell-antigen presenting cell contact and for T cell proliferation (Blood 2006;107:3212)
Uses: see above for bone marrow transplants
Positive staining (normal): low levels on immature (cortical) thymocytes, high levels on mature (medullary) thymocytes; also mature T cells, B cell subset (B1a cells), CNS cells
References: OMIM 186720
Member of immunoglobulin superfamily at 17q25.2-25.3
Has costimulatory activity for T cells (Immunol Res 2001;24:31)
Membrane expression early during T cell development, before TCR rearrangement; persists until terminal stages of T cell development
Plays important role in T cell-B cell interaction in early lymphoid development
Downregulated in infectious mononucleosis (AJCP 2003;120:49)
Loss of CD7 expression and altered cellular glycosylation may contribute to apoptosis resistance of malignant T cells in mycosis fungoides (Mod Path 2003;16:543)</