Immunology - Nomenclature

AMA Manual of Style - Stacy L. Christiansen, Cheryl Iverson 2020

Immunology
Nomenclature

14.8.1 Chemokines.

Chemokines comprise a family of more than 40 low-molecular-weight cytokines (see 14.8.4, Cytokines) with important roles in the immune system and functions beyond it.1,2,3,4,5,6 The name chemokine, a contraction of “chemotactic cytokine,” reflects the common property, by which they were originally identified, of promoting leukocyte chemotaxis.

Chemokines are defined by structure, not function, and are classified into 4 subfamilies based on their cysteine (C) residues and other amino acid (X) residues (see 14.6.1, Nucleic Acids and Amino Acids):

CXC

1 amino acid residue between the 2 N-terminal cysteines

CC

N-terminal cysteines adjacent

XC

cysteines 1 and 3 not present

CX3C

3 amino acids between the cysteine residues

The group names are roots followed by the letter L and a number (eg, CXCL1).4(p146)

Examples of specific chemokines, by subfamily, are given in Table 14.8-1.

Table 14.8-1. Examples of Specific Chemokines by Subfamily

Subfamily name

Synonym

Examples5

Receptors

Systematic name

Common names and abbreviation

CXC

α class

CXCL1

growth-related oncogene α (GRO-α), melanoma growth stimulatory activity protein (MGSA)

CXCR2

CXCL4

platelet factor 4 (see 14.7, Hemostasis)

NA

CXCL5

epithelial cell—derived neutrophil attractant 78 (ENA-78)

CXCR2

CXCL6

granulocyte chemoattractant protein 2 (GCP-2)

CXCR1, CXCR2

CXCL8

interleukin 8 (IL-8) (see 14.8.4, Cytokines)

CXCR1, CXCR2

CXCL14

chemokine isolated from breast and kidney tissue (BRAK), bolekine

NA

CC

β class

CCL1

inducible 309 (I-309)

CCR8

CCL3

macrophage inflammatory protein 1a or 1α (MIP-1α)

CCR1, CCR5

CCL5

regulated on activation of normal T cells expressed and secreted (RANTES)

CCR1, CCR3, CCR5 (also called CD195; see 14.8.2, CD Cell Markers)

CCL7

monocyte chemoattractant (or chemotactic) protein 3 (MCP-3)

CCR1, CCR2, CCR3

CCL21

secondary lymphoid tissue chemokine (SLC), chemokine β-9 (CKβ-9), exodus 2, 6Ckine

CCR7 (also called CDw107; see 14.8.2, CD Cell Markers)

XC

γ class

XCL1

lymphotactin, activation-induced, T-cell—derived, and chemokine-related (ATAC), single cysteine motif 1α (SCM-1α)

XCR1

XCL2

single cysteine motif 1β (SCM-1β)

XCR1

CX3C

δ class

CX3CL1

fractalkine

CX3CR1

Abbreviation: NA, not applicable.

Expanded common names of the chemokines are often unwieldy and uninformative and so are rarely used, although use of the abbreviations persists. Terms such as those in Table 14.8-1 for chemokine, chemokine subfamily, and chemokine receptor do not need to be expanded, but context should be provided at first mention:

the CXC chemokine family

the chemokine CXCL1

chemokine receptor CXCR2

14.8.2 CD Cell Markers.

CDs (clusters of differentiation) are a system for identifying cellular surface markers, a number of which define lymphocyte subsets (see 14.8.7, Nomenclature, Lymphocytes).7,8,9,10,11,12 The system and its nomenclature were formalized in a 1982 international workshop. Originally, CD terms specified the monoclonal antibodies (mAbs) that clustered statistically in their reactivities to target cells. More recently, the CD terms apply to the cellular molecules themselves. The CDs, which now number nearly 400 (and may eventually number in the thousands12), are defined at the Human Cell Differentiation Molecules workshops (formerly Human Leukocyte Differentiation Antigen Workshops). Workshops involve “multiple laboratories examining coded panels of antibodies [with] multilaboratory blind analysis and statistical evaluation of the results.”11(p226) Although reactivity and cellular expression originally were key in identifying CDs, gene-based molecular relatedness has become an important determinant.11,12 See the Human Cell Differentiation Molecules website for updates on the most recent workshop and conference, including confirmed, validated antibodies and newly assigned CDs.13

Some CDs are known most commonly by their CD designation. Other molecules have been assigned CD numbers retroactively; although they will be referred to by their common names, it is useful for authors to include the CD designations.11 Terms related to CDs do not need to be expanded. See the examples in Table 14.8-2.

Table 14.8-2. Examples of Terms Related to Clusters of Differentiation

CD terms

Other name(s)13,14

CD1a

CD1, CD1A

CD3d

CD3D, CD3-delta, T3D

CD4

NA (see 14.8.7, Lymphocytes)

CD6

TP120

CD8a

CD8A,CD8, p32 (see 14.8.7, Lymphocytes)

CD10

membrane metalloendopeptidase (MME), CALLA (common acute lymphoblastic leukemia antigen), CD10, neprilysin (NEP), enkephalinase

CD16a

FCGR3A (an Fc receptor; see 14.8.6, Immunoglobulins), FCG3, FCGR3, CD16

CD35

complement receptor type 1 (CR1; see 14.8.3, Complement), C3BR, CD35

CD41

glycoprotein IIb (see 14.1.2, Platelet-Specific Antigens), GP2B, GPIIb, CD41B

CD44R

CD44 variant, CD44v1-10

CD46

membrane cofactor protein (MCP; see 14.8.3.3, Complement Regulators), MGC26544

CD50

intracellular adhesion molecule 3 (ICAM-3)

CD55

delay accelerating factor (DAF; see 14.8.3, Complement)

CD62P

CD62, PSEL (P selectin), granule membrane protein 140 (GMP-140), GRMP

CD79a

Igα (see 14.8.6, Immunoglobulins); MB-1

CD97

TM7LN1

CD107a

lysosomal-associated membrane protein 1 (LAMP-1), CD107A

CD120a

tumor necrosis factor receptor (TNF-R) type 1, TNFR

CD139

NA

CD195

CCR5 (see 14.8.1, Chemokines)

CD213a2

IL-13Ra2 (see 14.8.4, Cytokines)

CD220

NA

CD235a

glycophorin a (GPA)

CD240CE

Rh blood group, CcEe antigens (see 14.1.1, Blood Groups)

Abbreviation: NA, not available.

A lowercase w (for “workshop”) signifies a provisional cluster (which is likely to become final, and have the w dropped, in an upcoming workshop11):

CDw186

The new designation of CDw128a is CD181.

Complexes of more than 1 CD molecule are indicated with a virgule:

CD11a/CD18 (leukocyte functional antigen 1 [LFA-1])

CD11b/CD18 (CR3 or C3bi receptor; see 14.8.3, Complement)

CD49c/CD29

The CD nomenclature displaced previous terms, for example, CD8 for T8 or OKT8, CD4 for T4 or OKT4, CD5 for Leu-1, Lyt-1, and CD5 for T1.

For therapeutic monoclonal antibody nomenclature, see 14.4, Drugs.

14.8.3 Complement.

The term complement refers to a group of serum proteins activated sequentially and rapidly in a cascade that produces molecules providing resistance to pathogens.15 The system was named in 1899 for its complementarity with antibodies in destroying microbes.15

Current nomenclature derives largely from the 1968 World Health Organization Bulletin “Nomenclature of Complement,”16 with subsequent modifications as mechanisms of action were further elucidated.

Three complement activation pathways are recognized: the classical pathway (activation by antibody), the alternative pathway (despite the name, the more phylogenetically ancient), and the lectin pathway. They culminate in a common terminal pathway. Components of the classical and terminal pathways are designated with a C and a number, reflective of the order of discovery of the component rather than the reaction sequence. (The prime, as in C′, has been discontinued.) Letters and abbreviations other than C typify the components of the other pathways. Complement component terms need not be expanded:

Classical

C1, C4, C2

Alternative

factors D, B, P (P for properdin [“destruction-bringing”14])

Lectin or MB lectin

mannose-binding lectin (MBL), MBL-associated serine protease 1 (MASP-1), MASP-2, MASP-3

Terminal

C5, C6, C7, C8, C9 C3 (common to all pathways)

14.8.3.1 Fragments.

Appended lowercase letters indicate complement fragments. Usually, a lowercase b indicates the larger, active (membrane-binding) fragment and a lowercase a, the smaller, release fragment (released on cleavage of the parent molecule). However, C2 is inconsistent: C2a is the larger active fragment and C2b the smaller release fragment. Other letters represent fragments of b fragments.

C3a

C3b

C3c

C3d

Cdg

C3f

C4a

C4b

C4c

C4d



C5a

C5b






Bb





14.8.3.2 Subunits.

The subunits of C1 are as follows:

C1q C1r C1s

Various notations that combine the C1 subunits convey the stoichiometry (relative quantities of subunits) of the complex; all such styles are acceptable:

(C1r)2

C1r2C1s2

C1qC1r2C1s2

C1qr2s2

C1s-C1r-C1r-C1s

Isotypes of C4 have capital letters appended:

C4A C4B

Protein chains have Greek letters appended:

C8α

C8β

C8γ

C3α is the α chain of C3.

Cleavage of C3α produces C3a and C3b.

An i signifies inactive forms:

iC3 or C3i

iC3b

Complement components that form a complex are written in a series without spaces:

C4b2a3b

C4bC2

Sometimes a hyphen is used to indicate a series:

C5b67 or C5b-7

C5-9

An asterisk shows nascent or metastable state:

C4b*

C3b*

C5b*

C5b-7*

Convertase complexes are linked complement fragments that activate other complement components. For example, the convertase that activates C3 is known as C3 convertase. As in the following examples, the convertases have different compositions, depending on which complement pathway generated them:

C3 convertase

Classical pathway, C4b2a; alternative pathways, C3bBb, C3bBbP, C3(H2O)Bb(Mg2+)

C5 convertase

Classical pathway, C4b2a3b; alternative pathways, C3bBbC3b, (C3b)2Bb

Note: Occasionally, authors have changed the designation of the activated moiety of C2 from C2a to C2b, to be consistent with other complement components.17,18(p8) A tipoff to the change is the designation of classical pathway C3 convertase as C4b2b.

14.8.3.3 Complement Regulators.

Complement regulators include those listed in Table 14.8-3.

Table 14.8-3. Examples of Complement Regulators

Name

Other terms

C1 inhibitor (C1-INH)a

C1 esterase inhibitor, C1 esterase INH

C3 membrane proteinases

NA

C4 binding protein (C4bp)

NA

carboxypeptidases

NA

CD59

membrane inhibitor of reactive lysis (MIRL), membrane attack complex—inhibitory factor (MACIF), homologous restriction factor 20 (HRF20), P18, protectin

decorin

NA

delay accelerating factor (DAF)

CD55

factor H

formerly β1H

factor I [letter I, not roman numeral “one”]

NA

factor H—like protein (FHL-1)

NA

membrane cofactor protein (MCP)

CD46

S proteina

vitronectin

SP-40,40

clusterin

Abbreviation: NA, not applicable.

a Not the same as protein S (see 14.7.4, Inhibition of Coagulation and Fibrinolysis).

14.8.3.4 Complement Receptors.

Complement receptors include those listed in Table 14.8-4.

Table 14.8-4. Examples of Complement Receptors

Name

Other terms

complement receptor type 1 (CR1)

C3b receptor, CD35

CR2

C3d receptor, CD21, CD21S (short isoform), CD21L (long isoform)

CR3

Mac-1, CD11b/CD18

CR4

p150/95, CD11c/CD18

C3aR

NA

C4aR

NA

C5aR

CD88

cC1qR

collectin receptor; c prefix: collagen region of C1q

gC1qR

g prefix: globular head portion of C1q

C1qRp

NA

factor H receptor (fH-R)

NA

Abbreviation: NA, not applicable.

14.8.4 Cytokines.

Cytokines are proteins or glycoproteins produced after stimulation (such as activation of immune cells) that act at short distances in low concentrations to produce various effects, such as immune and inflammatory reactions, repair processes, and cell growth and differentiation.4,6,19,20,21,22 Like hormones, cytokines are growth factors. Each cytokine has multiple effects and overlaps with other cytokines, including structurally dissimilar ones, in those effects. The multiple effects (pleiotropy) are explained by the presence of cytokine receptors on a wide variety of cells and the overlap (redundancy) by structural similarities of the intracellular portions of cytokine receptors.23

Cytokines were originally named by function. Because of their multiple and overlapping functions,19 the interleukin nomenclature24,25 was proposed to simplify terminology of this major class of cytokines and, it was hoped, subsequent regulatory immune system proteins. The more recent grouping of cytokines by receptor families and signaling pathways, however, does not necessarily correspond to previous groupings (eg, the interleukins fall into more than one family).

14.8.4.1 Cytokine Families and Subfamilies.

Molecular similarity of cytokine receptors has resulted in their grouping into families and subfamilies23:

chemokine families (see 14.8.1, Chemokines)

colony-stimulating factor (CSF)

interleukin 1/toll-like receptors (IL-1/TLR)

platelet-derived growth factor family (PDGF)

receptor tyrosine kinases

transforming growth factor β (TGF-β) receptor serine kinase family

tumor necrosis factor (TNF)

type 1 (hematopoietins)

 βc-utilizing (common cytokine receptor β chain)

 γc-utilizing (common cytokine receptor γ chain)

 gp130-utilizing

 heterodimeric

 homodimeric

type 2 (interferons; IL-10 family receptors)

 heterodimeric

Cytokine signaling pathways are associated with families and subfamilies (Table 14.8-5).

Table 14.8-5. Cytokine Signaling Pathways and Associated Families

Cytokine signaling pathways

Expansion or origin of term

Associated cytokine family

caspases


TNF

FADD

Fas-associated death domain

TNF

FAST-1

forkhead activin signal transducer

TGF-β receptor serine kinase family

IRAK

IL-1 receptor—associated kinase

IL-1/TLR

Jak1

Janus kinase 1

type 1

Jak2

Janus kinase 2

type 1

Jak3

Janus kinase 3

type 1

MyD88

myeloid differentiation marker

IL-1/TLR

NF-κB

nuclear factor—κB

IL-1/TLR

Ras/Raf/MAPK

ras protein, raf protein (see 14.6.3, Oncogenes and Tumor Suppressor Genes), mitogen-activated protein kinases

type 1, receptor tyrosine kinases

SARA

SMAD anchor for receptor activation

TGF-β receptor serine kinase family

SMADs

mothers against decapentaplegic (dpp) signaling (MAD) in Drosophila and Sma genes from Caenorhabditis elegans26

TGF-β receptor serine kinase family

STAT1

signal transducer and activator of transcription 1

type 1

STAT2


type 1

STAT3


type 1

STAT4


type 1

STAT5


type 1

STAT5a


type 1

STAT5b


type 1

STAT6


type 1

TAK1

TGF-β—associated kinase

TGF-β receptor serine kinase family

TRADD

TNF receptor—associated death domain

TNF

TRAFs

TNF-α receptor—associated factors

TNF

TRAF6


IL-1/TLR

Tyk2

tyrosine kinase 2

type 1

The pathway terms need not be expanded, but context should be clear at first mention:

the Jak1 signaling pathway

14.8.4.2 Chemokines.

See 14.8.1, Chemokines.

14.8.4.3 Colony-Stimulating Factors.

Colony-stimulating factors (CSFs) stimulate growth and differentiation of 1 or more blood cell types (neutrophils, eosinophils, monocytes/macrophages). Terms often, but not always, include the letters SF (eg, interleukins 3, 4, and 5—IL-3, IL-4, IL-5—which are also CSFs). Expand such terms at first mention:

granulocyte-macrophage colony-stimulating factor

GM-CSF

granulocyte colony-stimulating factor

G-CSF

macrophage colony-stimulating factor

M-CSF

14.8.4.4 Hormones.

These hormones are also considered cytokines:

erythropoeitin

Epo

growth hormone

GH

leptin


prolactin

PrL

thrombopoietin

Tpo

14.8.4.5 Interleukins.

A subset of cytokines were designated as interleukins in 1978 for “their ability to act as communication signals between different populations of leukocytes.”24(p2929) The interleukins have other biological effects as well. Their nomenclature was formalized in 1991.25 They are designated by number in order of discovery (eg, interleukin 1, interleukin 18, interleukin 29) but in general have no structural or functional association with one another. Although most have now been recognized as members of larger cytokine families, they retain their original designations. Specific interleukins are mentioned most commonly in their abbreviated form (note hyphen):

IL-1

IL-18

IL-29

The IL-1 family includes 2 forms of IL-1:

IL-1α

IL-1β

and the IL-1 receptor antagonist:

IL-1ra

Receptors for interleukins are designated, at minimum, with the interleukin name plus a capital R:

IL-2R

IL-4R

Receptor names designating subtypes may be even more specific:

IL-1RI

IL-1RII

Greek letters are used for subunits (chains) of the same receptor:

IL-2Rα

IL-2Rβ

IL-6Rα

IL-6Rβ

IL-12Rβ1

IL-12Rβ2

Terms for interleukins from different species should be expanded at first mention:

human IL-2

hIL-2

mouse IL-4

mIL-4

viral IL-10

vIL-10

For terminology for therapeutic interleukins, see 14.4.13, Nomenclature for Biological Products.

14.8.4.6 Interferons.

Interferons (IFNs) are another group of cytokines, originally discovered (and named) because of their interference with viral replication.

The type I IFNs, also known as antiviral interferons, are as follows:

IFN-α

IFN-β

IFN-λ1 (IL-29)

IFN-λ2 (IL-28A)

IFN-λ (IL-28B)

IFN-κ

IFN-ω

IFN-τ

Type II IFN, also known as immune interferon, is

IFN-γ

For terminology for therapeutic interferons, see 14.4.13, Nomenclature for Biological Products.

14.8.4.7 Other Cytokines.

Other cytokines and their abbreviations include the following:

cardiotrophin 1

CT-1

ciliary neurotrophic factor

CNTF

endothelial growth factor

EGF

fibroblast growth factor

FGF

FLT-3/FLT-2 ligand

FL

high-mobility group box chromosomal protein 1

HMGB-1

leukemia inhibitory factor

LIF

lymphotoxin α

LTα

oncostatin M

OSM

receptor activator of NF-κB ligand

RANKL

stem cell factor

SCF, c-kit ligand

transforming growth factor β

TGF-β, TGF-β1, TGF-β2, TGF-β3

tumor necrosis factor α

TNF-α

tumor necrosis factor β

TNF-β

vascular endothelial growth factor

VEGF

14.8.5 HLA/Major Histocompatibility Complex.

Antigens of what is known as the HLA system appear on virtually all nucleated cells of human tissues and on platelets. Just as red blood cell antigens determine blood type (see 14.1, Blood Groups, Platelet Antigens, and Granulocyte Antigens), HLA antigens determine tissue type.

HLA antigens were discovered to be determinants of the success of tissue transplantation (histocompatibility, histo- meaning “relating to tissue”). They were subsequently found to be critical for activating many immune responses, and certain HLA antigens are associated with particular diseases. Because of the great variation among individuals in these antigens (polymorphism), they have been used in forensic identification.

There are approximately 21 main polymorphic genes of interest in the HLA system that are encoded within a region of the short arm of chromosome 6 known as the major histocompatibility complex (MHC). More than 10 000 variants have been identified.27 The magnitude of this polymorphism distinguishes the HLA system from other gene families and has resulted in a detailed system for naming alleles and antigens.

Although HLA alleles were originally classified based on serologic and cellular assays, the current classification is based on DNA sequencing. Accordingly, in 1987, new nomenclature for these alleles consistent with the International System for Human Gene Nomenclature (see 14.6.2, Human Gene Nomenclature) was built onto the original nomenclature.28,29 A prime goal was for the nomenclature to reflect the association between serologically defined antigen specificities and those defined by DNA technology.30 With a large growth in the number of new alleles identified by DNA sequencing, many new alleles lack known serologic counterparts.31

14.8.5.1 Nomenclature.

Nomenclature of the HLA system, first formalized in 1967,32 is determined by the World Health Organization Nomenclature Committee for Factors of the HLA System. Full reports on HLA nomenclature, which present officially recognized antigens and alleles, appear annually, with monthly updates, in the journals Human Immunology, HLA (formerly Tissue Antigens), and International Journal of Immunogenetics; on the website of the Anthony Nolan Research Institute (https://www.anthonynolan.org/clinicians-and-researchers/anthony-nolan-research-institute); and at the IMGT/HLA Sequence database.27

14.8.5.1.1 HLA.

The abbreviation HLA has come to signify human leukocyte antigen(s). The original term was HL-A, the A being a simple letter designation, not an abbreviation for “antigen.”30 The term HLA applies to the locus of the human genome (MHC) that encodes specific HLA proteins and to the encoded proteins themselves. The term MHC is more generic, applicable to HLA molecules and their animal counterparts.

14.8.5.1.2 HLA Class I (MHC Class I Antigens).

The components of MHC class I molecules include the following:

■A polymorphic membrane-linked α chain or heavy chain, encoded within the MHC, comprising 3 domains: α1, α2, and α3

■A soluble invariant light chain called β-microglobulin (β2m); encoded on chromosome 15, not within the MHC locus

■A short peptide, typically 8 to 11 amino acids long, that is variable in sequence

There are 3 genes encoding MHC class I—like heavy chain that also associate with β2m:

class I genes:

HLA-A

HLA-B

HLA-C

There are 3 additional genes encoding class I—like heavy chain that also associate with β2m:

nonclassical (or class Ib):

HLA-E

HLA-F

HLA-G

14.8.5.1.3 HLA Class II (MHC Class II Antigens).

The components of an MHC class II molecule include the following:

■A polymorphic membrane-linked α chain with 2 domains: α1 and α2

■A polymorphic membrane—linked β chain with 2 domains: β1 and β2

■A peptide, typically approximately 13 to 17 amino acids long, that is variable in sequence

The α and β chains of class I and class II molecules are not identical, despite the similar naming conventions, but rather are distinct proteins. Both the α chain and the β chain of MHC class II molecules are encoded within the MHC. There are 3 pairs of human MHC class II genes:

class II genes:

HLA-DR

HLA-DQ

HLA-DP

14.8.5.1.4 Serologically Defined HLA Antigens.

Historically, antigen specificities of HLA class I molecules were defined serologically and indicated with numbers following the gene (major) locus letter(s), for example:

HLA-A1

HLA-B27

HLA-DR1

A w (for “workshop”) is used for serotype distinctions:

HLA-Bw4 and Bw6 distinguish distinct serotypes of HLA-B heavy chains

HLA-Cw1, HLA-Cw2, HLA-Cw3, etc, denote distinct serotypes

The term cross-reactive group (CREG) refers to serologically related groups of antigens. The abbreviation should be expanded at first mention. Note the following sample terms:

the HLA-A1 cross-reactive group (CREG)

the HLA-A2 CREG

the B5 cross-reactive group HLA-B51, B52, and B53

B7 CREG

Phrases such as the following may be used:

HLA-A, HLA-B, and HLA-C associations, which can denote disease associations with the presence of particular HLA class I genotypes

possible associations with HLA-B18, HLA-A2, and HLA-DQB1, which can denote disease associations with the presence of particular HLA class I or class II serotypes

testing for HLA-A (A2, A26) and HLA-B (B35, B44), which denotes testing for particular HLA class I serotypes

high prevalence of HLA-A1 (63%) and HLA-B8 (42%), which indicates frequencies of particular HLA class I serotypes within a test group

frequencies of HLA-A2 and A29, which refer to frequencies of indicated HLA class I serotypes within a test group

14.8.5.1.5 HLA Haplotypes.

The HLA haplotype is the set of HLA alleles on a given chromosome. Each person possesses 2 such haplotypes, 1 from each parent. Because of the high degree of polymorphism of the HLA class I and class II genes in the population, there are typically 2 different alleles of each of the class I and class II genes in an individual. When HLA typing is performed serologically, antigen specificities of the individual’s phenotype are presented as follows:

A3, A23, B51, B7, Cw2, Cw5, DR7, DR11

all antigens listed collectively

A23, B7, Cw5, DR7/A3, B51, Cw2, DR11

virgule separates antigens of one chromosome from those of other chromosome

A3, A23, B51, B7, Cw2, Cw5, DR11,-

hyphen indicates undetermined antigen

A1, B8, Cw4, DR17(3)/A2, B27, Cw5,-

DR for this haplotype not typed or untypable

A1, B8, Cw4, DR17(3)/A2, B27, Cw5, DR17(3)

2 identical DR specificities

Shorter haplotype expressions are shown below:

HLA-Cw6—bearing haplotype

the A1-B8-DR3 haplotypes

DRB1, DQA1, and DQB1 haplotypes

A25 B18 BFS DR11 haplotype

14.8.5.1.6 Other Histocompatibility Loci.

HLA antigens represent only some of the products of the MHC. Others, also important in immunity, are as follows:

Class I loci

MIC (MHC class I—related chain)

variants: MICA, MICB, MICC, MICD, MICE

Class II loci

TAP (transporter associated with antigen processing) and TAPBP are genes involved in the intracellular assembly of MHC class I molecules

TAP1 and TAP2 encode subunits of the TAP transporter

PSMB (proteosome-related sequence)

specificities: PSMB8 (formerly LMP7), PSMB9 (formerly LMP2), which encode interferon γ—inducible subunits of the proteasome, a proteolytic complex relevant to antigen presentation by HLA class I molecules

DM

DMA and DMB, encoding subunits of HLA-DM, important for the intracellular assembly of HLA class II molecules

DO

DOA and DOB, encoding subunits of HLA-DO, important for the intracellular assembly of HLA class I molecules

Class III loci (loci for 4 components of complement; see 14.8.3, Complement):

C2

C4 (2 genes: C4A and C4B)

Bf (B factor, properdin)

A haplotype of complement types is called a complotype, for example:

BfS, C2C, C4AQO, C4B1

(QO designates a deficiency.)

14.8.5.1.7 Genetic and Allele Nomenclature.

Use italics to distinguish HLA genes or gene loci from protein products (eg, HLA-A, HLA-DRB1) (see 14.6.2, Human Gene Nomenclature). The hyphen is retained in HLA gene expressions, an exception permitted in official gene nomenclature. Terms with asterisks indicate that HLA typing has been performed by molecular techniques. Terms with 2 digits (eg, A*02) indicate antigen typing with known serologic equivalent. Terms with 4 digits (eg, A*02:01) represent alleles. In contrast to other alleles, HLA alleles are usually not italicized. Authors should make clear from context whether the gene or its product is being discussed.

Table 14.8-6, adapted from Marsh,33 summarizes nomenclature for HLA designations.

Table 14.8-6. Nomenclature for HLA Designations

HLA

HLA region, prefix for an HLA gene

HLA-DRB1 or HLA-DRB1 or DRB1

A particular HLA locus, ie, DRB1 (B refers to the β-chain locus)

HLA-DRB1*13

A group of alleles that encode the DR13 antigen (antigen conferring DR13 specificity)

HLA-DRB1*13:01:02a

An allele that differs by a synonymous mutation from DRB1*13:01:01

HLA-DRB1*13:01:01:02

An allele that contains a mutation outside the coding region from DRB1*13:01:01:01

HLA-DRB1*13:01

A specific HLA allele

HLA-A*24:09N

A null (N) allele, an allele that is not expressed

HLA-A*30:14L

An allele encoding a protein with significantly reduced or low (L) cell surface expression

HLA-A*24:02:01:02L

An allele encoding a protein with significantly reduced or low cell surface expression, where the mutation is found outside the coding region

HLA-B*44:02:01:02S

An allele encoding a protein expressed as a secreted (S) molecule only


cytoplasm (C)b


aberrant (A) expressionb

HLA-A*32:11Q

An allele that has a mutation previously shown to have a significant effect on cell surface expression but where this has not been confirmed and its expression remains questionable (Q)

a Change from previous nomenclature: fifth digit only (2) for synonymous mutation. Former term: HLA-DRB1*13:01:2.

b As of March 2017, no alleles have been named with the C or A suffixes.33

For the HLA-D region, the gene name includes a letter for the chain that the gene codes for (A for α, B for β), often followed by a number for the chain gene (not the domain number, as described in the previous section on class I and class II molecules). For instance,

DRB1

gene for first DR β chain

DQA1

gene for first DQ α chain

The HLA prefix (including the hyphen) may be dropped from allele designations in series after first mention, eg:

comparative frequencies of HLA-DRB1*14, DQA1*03, DQA1*05, DQA1*01, DQB1*06

(not: HLA-DRB1*14 , -DQA1*03, -DQA1*05, -DQA1*01, -DQB1*06)

The conjunction and may be used to separate haplotypes but is not used before the final element in any single haplotype:

HLA-B38, DRB1*04:02, DRB4*01:01, DQB1*02:01, DQB1*03:02 (not and DQB1*03:02)

HLA-B38, DRB1*04:02, DRB4*01:01, DQB1*02:01, DQB1*03:02 and HLA-B*07:02, DRB1*16:01, DRB5*02, DQB1*05:02 haplotypes

The portion of the term before the asterisk may be dropped in a series, provided it would be the same in each term:

DRB4*01:01:01:01, *01:03:01:02N, *01:03:02, *01:03:03, *01:05

Commas signify and and virgules (forward slashes) signify or.34

Thus, commas indicate corresponding alleles from chromosome pairs (see 14.8.5.1.5, HLA Haplotypes), eg:

Donor: A*01, 02; B*08, 44; DRB1*01, 03; DRB3

Recipient: A*02, 11; B*40, 15; DRB1*09, 11; DRB3, DRB4

Virgules (forward slashes) indicate an ambiguous result in HLA typing, eg, the term A*02:01/02:03/02:05 means that A*02:01 or A*02:03 or A*02:05 is present.

Multiple alleles can encode serologically defined antigens. Also, alleles not defined serologically may have no known associated antigenic specificity. Examples of specificities and allele names are shown below.

A203

A*02:03

B78

B*78:01, B*78:02:01, B*78:02:02

B65(14)

B*14:02

B50(21)

B*50:01

DR53

DRB4 (various, eg, DRB4*01:02, *01:03:03)

none

the E alleles (E*01:01, 01:02, etc)

none

the F allele F*01:01

none

the G alleles (G*01:01:01, 01:01:02, etc)

HLA pseudogenes (see 14.6.2, Human Gene Nomenclature) resemble and are located near the HLA loci but are not transcribed to produce functional products. The class I pseudogenes end in letters after G, and the class II pseudogenes end in numbers after 1:

HLA-H

HLA-J

HLA-K

HLA-L

HLA-N

HLA-S

HLA-X

HLA-Z



HLA-DRB2

HLA-DRB6

HLA-DRB8

HLA-DRB9


HLA-DQA2

HLA-DQB2

HLA-DQB3

HLA-DPA2

HLA-DPB2








14.8.5.2 Animals.

In animals, major histocompatibility locus is abbreviated Mhc, using uppercase and lowercase.

The names for the Mhc in other animals35 usually correspond to the expression HLA for humans (but not always, eg, the prototypical mouse locus, H-2). In this convention, the name is based on a common name or species name combined with LA (leukocyte antigen):

cat

FLA

dog

DLA

domestic cattle

BoLA

domestic fowl

B

guinea pig

GPLA

horse

EqLA

mole rat

Smh

mouse

H-2

pig

SLA

rabbit

RLA

rat

RT1

Primate researchers use an alternative style based on the genus and species name (see 14.14, Organisms and Pathogens), which substitutes Mhc for LA.35 Note the examples in Table 14.8-7.

Table 14.8-7. Examples of Common Animal Terms

Common animal name

Species designation

Mhc term

Former LA term

chimpanzee

Pan troglodytes

MhcPatr

ChLA

gorilla

Gorilla gorilla

MhcGogo

GoLA

orangutan

Pongo pygmaeus

MhcPopy

OrLA

rhesus macaque

Macaca mulatta

MhcMamu

RhLA

14.8.6 Immunoglobulins.

Immunoglobulins are the Y-shaped glycoproteins on the surface of B cells (see 14.8.7.1, B Lymphocytes) that can be secreted as antibodies in response to an antigenic stimulus (any molecule or composition of molecules from pathogens: bacterium, virus, parasite, or from transplanted organ that are recognized by immunoglobulin). Secreted antibodies can bind specifically to their antigens and in some cases can neutralize pathogens. The immunoglobulins were first recognized by serum electrophoresis and, because they were localized to the electrophoretic gamma zone, were originally referred to as γ-globulins.36,37,38,39,40

Each immunoglobulin monomer contains 2 heavy chains and 2 light chains connected by disulfide bonds and abbreviated as follows:

H

L

Each H chain and L chain, in turn, contains both constant and variable regions, abbreviated as follows:

C

V

VH

variable region of heavy chain

VL

variable region of light chain

CH

constant region of heavy chain

CL

constant region of light chain

Heavy chains have 1 variable (VH) and 3 or 4 constant (CH) domains that are abbreviated as follows:

CH1

CH2

CH3

CH4

Light chains have 1 variable (VL) and 1 constant (CL) domain.

14.8.6.1 Immunoglobulin Antigen-Binding Site.

The VH and the VL domains of the immunoglobulin’s heavy and light chains have variable amino acid sequences, and together constitute the immunoglobulin antigen-binding site (Fab), also called immunoglobulin variable region (V).

There are 3 specific hypervariable regions within the variable regions of an immunoglobulin H or L chain that are known as complementarity-determining regions (CDRs) and are named as follows:

CDR1

CDR2

CDR3

Heavy- and light-chain CDRs are termed HDCR1, etc, and LDCR1, etc, respectively.

Four relatively invariable regions between hypervariable regions are called framework regions and are designated as follows:

FR1

FR2

FR3

FR4

14.8.6.2 Immunoglobulin Constant Regions

The CH and CL domains of the carboxyl terminal of an immunoglobulin’s heavy and light chains have an amino acid sequence that does not vary within a given class or subclass of immunoglobulin and are called immunoglobulin constant (C) regions. The carboxyl-terminal tail CH regions of 2 immunoglobulin heavy chains are called the immunoglobulin Fc region.36(p2673)

Enzyme cleavage and antibody engineering result in fragments of the immunoglobulin molecule with specific names. Expansion of these terms is not necessary.

Fab

antigen-binding fragment

Fab′

Fab with part of hinge region (flexible amino acid stretch in the central part of the IgG and IgA heavy chains, which links these 2 chains by disulfide bonds)

F(ab′)2

2 linked Fab′ fragments

Fabc


Fb

constant part of Fab fragment

Fc

crystallizable fragment

pFc′

fragment that includes Fc that is formed by pepsin cleavage; the remaining fragment is F(ab′)2

Fd

portion of the heavy chain that is included in Fab fragment

Fv

variable part of Fab fragment

scFv

single-chain Fv, not Ab fragment; a fusion protein of VH and VH connected with a short peptide linker

14.8.6.3 Heavy Chains.

There are 5 different classes of immunoglobulins that differ in the sequence and structure of their heavy-chain constant regions (CH). The type of heavy chain identifies the class (isotype) of immunoglobulin. Heavy chains are named with the Greek letter that corresponds to the class of immunoglobulin. These are listed below from the most to the least abundant antibodies in human serum41,42:

γ

IgG

α

IgA

μ

IgM

γ

IgD

ε

IgE

IgG and IgA subclasses and corresponding heavy chains are as follows:

γ1

IgG1

γ2

IgG2

γ3

IgG3

γ4

IgG4

α1

IgA1

α2

IgA2

CH domains may be specified according to isotype. For example,

Cε2

Cμ4

Cα3

Cγ3

The 2 transmembrane accessory proteins associated with surface immunoglobulins on some immune cells should not be confused with terms for immunoglobulin classes or heavy chains:

Igα (immunoglobulin-associated α, CD79a; this is not IgA or the α heavy chain)

Igβ (immunoglobulin-associated β, CD79b)

14.8.6.4 Light Chains.

There are 2 types of light chain (named for initials of the discoverers’ surnames43):

κ

λ

Both types of light chain are associated with all 5 immunoglobulin classes; that is, an immunoglobulin molecule of any type might have κ or λ light chains (but not both types in the same molecule). In humans, there are 6 classes (isotypes) of λ chain:

λ1

λ2

λ3

λ4

λ5

λ6

CL and VL regions may be specified by light chain type, as follows:

Cκ

Cλ

Vκ

Vλ

Serologic markers and their associated chains are indicated with roman letters and a lowercase m:

G1m

γ1

G2m

γ2

G3m

γ3

A2m, A2m(1), A2m(2)44

α2

Em

ε

Km

κ

14.8.6.5 Other Immunoglobulin Components.

The secretory forms of IgM and IgA contain an additional polypeptide, the J chain (not to be confused with the joining or J segments of the immunoglobulin gene loci; see 14.8.6.9, Immunoglobulin Genetics).

Secreted IgA also contains a secretory component, SC.

14.8.6.6 Molecular Formulas.

Different immunoglobulin isotypes could be secreted as monomers (IgG, IgA, IgE, IgD), dimers (IgA), or pentamers (IgM). The formulas below indicate the number of polypeptide chains that constitute an immunoglobulin molecule:

γ2L2

IgG monomer with 2 γ chains and 2 light chains

α2L2

IgA monomer with 2 α chains and 2 light chains

2L2)2SCJ

IgA dimer with 4 α chains, 4 light chains, an SC, and a J chain

2L2)5

IgM pentamer with 10 μ chains and 10 light chains

2L2)5J

IgM pentamer with 10 μ chains, 10 light chains, and a J chain

δ2κ2

IgD monomer with 2 δ chains and 2 κ light chains

ε2λ2

IgE monomer with 2 ε chains and 2 λ light chains

14.8.6.7 Ig Prefixes.

The following are examples of terms combining Ig and a single-letter prefix. It is best to expand these terms at first mention (especially those with the letters m or s, each of which has more than 1 meaning):

mIgM

monomeric IgM

mIgM

membrane-bound IgM

pIg

polymeric immunoglobulin

pIgA

polymerized IgA

pIgR

receptor for polymeric immunoglobulin

sIg

surface immunoglobulin

sIgM

surface IgM

sIgA

secretory IgA

14.8.6.8 Fc Fragments and Fc Receptors.

Immunoglobulins bind to the Fc receptors expressed on the accessory cells via their FC regions and modulate functions of the cells. Fc fragments may be specified by the heavy chain class from which they arise45:

Fcγ1

Fcγ2

Fcγ3

Fcγ4

Fcα1

Fcα2



Fcμ




Fcδ




Fcε




Receptors for the Fc portion of immunoglobulin molecules are named as follows (cell surface marker identities, if applicable, are shown in parentheses; see 14.8.2, CD Cell Markers):

IgG receptors:

FcγRI

(CD64)


FcγRII

(CD32)


FcγRIIIA

(CD16a)


FcγRIIIB

(CD16b)

IgA receptor:

FcαR

(CD89)

IgM receptor:

FcμR


IgE receptors:

FcεRI



FcεRII

(CD23)

14.8.6.9 Immunoglobulin Genetics.

Immunoglobulin H-chain and L-chain gene loci consist of families of gene segments, sequentially arrayed along the chromosome, with each set of segments containing alternative versions of the immunoglobulin V region. The 2 types of gene segment that encode the L-chain V region are called variable (V) and joining (J) gene segments. The H-chain locus includes an additional set of diversity (D) gene segments that lies between the arrays of V and J gene segments. These gene segments encoding the L-chain variable region can be referred to as follows:

VL

JL

CH (or Vκ

Vλ

Jκ)

These gene segments encoding the H-chain variable region can be referred to as follows:

VH

DH

JH

Downstream of the gene segments encoding immunoglobulin variable region, there are segements of genes encoding constant immunoglobulin region. Heavy chain constant region gene segments contain regions encoding various classes (isotypes) of immunoglobulins and can be referred to as follows (the subscript number refers to the isotype subtype):

Cγ2

Cμ

Cα2

Subgroups (various nonallelic forms) of V, D, J, and C gene segments are specified numerically (subscript numbers refer to the class of Ig, online numbers refer to the subgroup), as follows:

Vκ1

Vλ3

DH1

DH3

Jκ2

JH1 Cα25

Cλ11

Cλ2

A superscript plus sign may be used to indicate expression of a specific segment, eg, by a particular B lymphocyte (see 14.8.7, Lymphocytes):

Vκ3+

The V, D, and J gene segments are brought together by DNA rearrangement. Descriptive terms for this process include the following:

V/J exon, segment, region, gene, recombination

in L-chain genes

V/D/J exon, segment, region, gene, recombination

in H-chain genes

V/(D)/J

L- and/or H-chain genes

VDJ, V/D/J,V-D-J, variable-diversity-joining

alternative terms

A leader segment (L), which codes for a leader (L) peptide, precedes each V segment.

Note the following potential sources of confusion:

V, D, and J segments code for the variable (V) region of an immunoglobulin protein.

J segment does not refer to the J chain of the secretory forms of IgA and IgM (see 14.8.6.5, Other Immunologic Components).

L (leader) gene segment and L (light) immunoglobulin chain are different entities. (Subscript L’s, as in various terms in this section, typically refer to the light chain.)

14.8.6.10 Official Gene Terminology.

Official gene symbols for specific genes of the types discussed above are presented in Table 14.8-8 (see 14.6.2, Human Gene Nomenclature). Follow author usage.

Table 14.8-8. Examples of Official Gene Symbols and Immunogenetic Terms

Official gene symbol

Immunogenetic term

IGHA1

Cα1

IGHD

Cδ

IGHD1-1

member of DH1 subgroup

IGHE

Cε

IGHG1

Cγ1

IGHJ1

JH1

IGHV@

VH

IGHV1-2

member of VH1 subgroup

IGKC

Cκ

IGKJ@

Jκ

IGKJ2

Jκ2

IGKV@

Vκ

IGKV1-5

member of Vκ1 subgroup

IGLC@

Cλ

IGLC1

Cλ1

IGLJ@

Jλ

IGLJ1

Jλ1

IGLV@

Vλ

IGLV1-36

member of Vλ1 subgroup

14.8.6.11 Alleles.

Alleles are indicated with an asterisk and number following the gene name:

IGHA1*01

IGHD*02

IGHD1-7*01

IGLJ1*01

IGLV2-11*01

For more detailed molecular information about immunoglobulin genetics, consult the International ImMunoGeneTics database.46

14.8.7 Lymphocytes.

Lymphocytes are the cells that carry out antigen-specific immune responses.47,48,49 The 2 main types are the T lymphocyte and the B lymphocyte, also called the T cell and the B cell. A hyphen does not appear in these terms, unless they are used adjectivally. The terms are not customarily expanded.

T lymphocyte

T cell

T-cell lymphoma

B lymphocyte

B cell

B-cell signaling

Historically, the letters T and B reflected the anatomic sites of maturation of the 2 groups of cells, the thymus and the bursa of Fabricius, respectively. (The bursa of Fabricius is a specialized organ in birds.) Because in human adults B cells mature in the bone marrow, the letter B is sometimes taken as signifying bone marrow.

A third group of lymphocytes is known as natural killer cells, abbreviated NK cells.

14.8.7.1 B Lymphocytes.

In the context of B-lymphocyte development, the prefixes pre- and pro- are encountered; note hyphenation:

pro-B cell

pre-B cell

B-cell subsets are named in various ways, eg:

CD5+ B cells

B1 B cells

MZ B cells

B-cell antigen receptors (BCRs) are membrane complexes of membrane immunoglobulins and the molecules Igα and Igβ (see 14.8.6, Immunoglobulins).

14.8.7.2 T Lymphocytes.

The main types of T lymphocyte are as follows (expand at first mention):

helper T cells:

TH cells

cytotoxic T cells:

TC cells, also called cytotoxic lymphocytes (CTL)

Most helper T cells express the cell marker CD4, and most cytotoxic T cells express the cell marker CD8 (see 14.8.2, CD Cell Markers), giving rise to the following terms:

CD4 T cells

CD8 T cells

When presence or absence of a marker on a T cell is emphasized, superscript plus or minus signs are used. Presence and absence of the CD4 and CD8 markers are often indicated by the terms positive and negative (eg, double-positive lymphocytes), as shown in Table 14.8-9.

Table 14.8-9. Examples Indicating Presence or Absence of CD4 or CD8 Markers

CD4+



CD4



CD4+CD8

single positive

a CD4 cell

CD4CD8+

single positive

a CD8 cell

CD4CD8

double negative


CD2+CD4CD8

double negative


CD4+CD8+

double positive


CD2+CD4+CD8

single positive

a CD4 cell

CD2+CD4CD8+

single positive

a CD8 cell

CD3+CD4+CD8

single positive

a CD4 cell

CD3+CD4CD8+

single positive

a CD8 cell

Because other cells (eg, monocytes) may express CD4, authors should use terms more specific than “CD4 cells,” unless context has made clear which cells are referred to, eg:

CD4 lymphocyte count (not CD4 cell count)

Subtypes of helper T cells are as follows:

TH0

TH1

TH2

TH17

Treg


The theoretical helper T precursor to these subtypes is abbreviated:

THp

14.8.7.3 T-Cell Receptors.

T-cell receptors (TCRs) are protein complexes on the surface of T cells.50 The T-cell receptor—CD3 complex (abbreviated TCR-CD3) is a structure that recognizes antigen. Its subunits, or chains, are designated by Greek letters:

α chain

β chain

γ chain

δ chain

ε chain

ζ chain

η chain

(Do not confuse these chains with the components of MHC or Ig molecules, although there is some homology among them; see 14.8.5, HLA/Major Histocompatibility Complex, and 14.8.6, Immunoglobulins.)

The α and β chains are also referred to as follows:

TCRα and TCRβ

Linked α and β chains and linked γ and δ chains result in these terms:

αβ dimer

γδ dimer

αβ heterodimer

γδ heterodimer

αβ receptor

γδ receptor

αβ cell

γδ cell

αβ T cell

γδ T cell

T αβ T

γδ

CD8αβ


The γ, δ, ε, ζ, and η chains constitute the CD3 complex. The CD3 chains are also referred to individually and as dimers:

CD3γ

CD3δ

CD3ε

CD3ζ

CD3η

CD3γε

CD3δε

CD3ζζ

CD3ζη


There are 2 subtypes of the γ chain:

γ1

γ2

The TCR protein has variable (V) and constant (C) regions or domains. The gene for TCRα is made up of variable (V), joining (J), and constant (C) segments, as is the β chain, which also has a diversity (D) segment. (These are analogous to the segments of the immunoglobulin genes; see 14.8.6, Immunoglobulins.) These segments may also be referred to as follows:

Vα

Vβ

Jα

Jβ

Dβ

Cα

Cβ

Subgroups (various nonallelic forms) of the V, D, or J segments are specified numerically, eg:

Vα2

Jβ7

T-cell expression of a particular segment may be indicated by using a superscript plus sign:

Vβ2+

14.8.7.4 T-Cell Receptor Gene Terminology.

Because the V, D, and J gene segments together encode the variable (V) region of the protein, it is unusual to refer to D or J regions of the protein.50

The V, D, and J gene segments are brought together by DNA rearrangement. Descriptive terms include the following:

V/J exon, segment, region, gene, recombination

for α or γ chain genes

V/D/J exon, segment, region, gene, recombination

for β or δ chains

V/(D)/J

of α and γ or β and δ chains

VDJ, V/D/J,V-D-J, variable-diversity-joining

alternative terms

14.8.7.5 Official Gene Terminology.

Official gene symbols for specific genes of the types discussed above are presented in 14.6.2, Human Gene Nomenclature. The TCR genes begin with TR and use roman letters that correspond to the Greek letters of the TCR component chains, and they contain V, C, D, and J corresponding to the above terms. Like other immune genes, they may contain hyphens:

TRAC

TRBC

TRBV10-3

TRGC1

TRGJ

TRDC

14.8.7.6 Alleles.

Alleles are indicated with an asterisk and number following the gene name:

TRBV7-1*01

Principal Author: Cheryl Iverson, MA

Acknowledgment

Thanks to Preeti Malani, MD, MSJ, JAMA, and Department of Internal Medicine, University of Michigan, Ann Arbor; Irina Grigorova, PhD (Immunoglobulins and B Cells), Department of Microbiology and Immunology, University of Michigan, Ann Arbor; Malini Raghavan, PhD (HLA Antigens), Department of Microbiology and Immunology, University of Michigan, Ann Arbor; and Cheong-Hee Chang, PhD (T Lymphocytes), Department of Microbiology and Immunology, University of Michigan, Ann Arbor, for reviewing and providing comments.

References

1.IUIS/WHO Subcommittee on Chemokine Nomenclature. Chemokine/chemokine receptor nomenclature. J Interferon Cytokine Res. 2002;22(10):1067-1068. doi:10.1089/107999002760624305

2.Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12(2):121-127. doi:10.1016/S1074-7613(0 0)80165-X

3.Murphy PM. Chemokines. In: Paul WE, ed. Fundamental Immunology. 7th ed. Lippincott Williams & Wilkins; 2013:681-707.

4.Rich RR, Fleisher T, Shearer WT, Schroeder HW Jr, Frew AJ, Weygand CM, eds. Clinical Immunology: Principles and Practice. 4th ed. WB Saunders; 2013.

5.Thomson AW, Lotze MT. The Cytokine Handbook. 4th ed. Academic Press; 2003.

6.Cytokine Family Database (dbCFC). Published August 3, 2010. Accessed October 18, 2019. http://cmbi.bjmu.edu.cn/cmbdata/cgf/CGF_Database/cytokine.medic.kumamoto-u.ac.jp/default.htm

7.Bernard A, Boumsell L. The clusters of differentiation (CD) defined by the First International Workshop on Human Leukocyte Differentiation Antigens. Hum Immunol. 1984;11(1):1-10. doi:10.1016/0198-8859(84)90051-X

8.Bernard A, Bernstein I, Boumsell L, et al. Differentiation human leukocyte antigens: a proposed nomenclature. Immunol Today. 1984;5(6):158-159. doi:10.1016/0167-5699(84)90002-1

9.IUIS/WHO Subcommittee on CD Nomenclature. Nomenclature for clusters of differentiation (CD) of antigens defined on human leukocyte populations. Bull World Health Organ. 1984;62(5):809-811.

10.Singer NG, Todd RF, Fox DA. Structures on the cell surface: update from the Fifth International Workshop on Human Leukocyte Differentiation Antigens. Arthritis Rheum. 1994;37(8):1245-1248. doi:10.1002/art.1780370820

11.Zola H. The CD nomenclature: a brief historical summary of the CD nomenclature, why it exists and how CDs are defined. J Biol Regul Homeost Agents. 1999;13(4):226-228.

12.Zola H, Swart B. The human leucocyte differentiation antigens (HLDA) workshops: the evolving role of antibodies in research, diagnosis and therapy. Cell Res. 2005;15(9):691-694. doi:10.1038/sj.cr.7290338

13.HCDM: Human Cell Differentiation Molecules website. Accessed July 31, 2019. http://www.hcdm.org

14.HUGO Nomenclature Committee. Gene family: CD molecules. Accessed July 31, 2019. https://www.genenames.org/cgi-bin/genefamilies/set/471

15.Morgan BP. Complement. In: Paul WE, ed. Fundamental Immunology. 7th ed. Lippincott Williams & Wilkins; 2013:863-890.

16.World Health Organization. Nomenclature of complement. Bull World Health Organ. 1968;39(6):935-938.

17.Letendre P. Complement: to be or not to be? Transfusion. 1990;30(5):478-479. doi:10.1046/j.1537-2995.1990.30590296388.x

18.Playfair JHL, Lydyard PM. Medical Immunology Made Memorable. 2nd ed. Churchill Livingstone; 2000.

19.Oppenheim JJ, Feldmann M. Introduction to the role of cytokines in innate host defense and adaptive immunity. In: Durum SK, Hirano T, Vilcek J, Nicola NA, eds. Cytokine Reference: A Compendium of Cytokines and Other Mediators of Host Defense. Academic Press; 2001:3-20.

20.Leonard WJ. Type I cytokines and interferons, and their receptors. In: Paul WE, ed. Fundamental Immunology. 7th ed. Lippincott Williams & Wilkins; 2013:601-638.

21.Ware CF. Tumor necrosis factor—related cytokines in immunity. In: Paul WE, ed. Fundamental Immunology. 7th ed. Lippincott Williams & Wilkins; 2013:659-680.

22.O’Shea JJ, Gadina M, Siegel R. Cytokines and cytokine receptors. In: Rich RR, Fleisher TA, Shearer WT, Schroeder HW Jr, Frew AJ, Weygand CM, eds. Clinical Immunology: Principles and Practice. 4th ed. WB Saunders; 2013:108-135.

23.Fitzgerald KA, O’Neill LAJ, Gearing AJH, Callard RE. The Cytokine FactsBook. 2nd ed. Academic Press; 2001.

24.Aarden LA, Brunner TK, Cerottini J-C, et al. Revised nomenclature for antigen-nonspecific T cell proliferation and helper factors. J Immunol. 1979;123(6):2928-2929.

25.Paul WE, Kishimoto T, Melchers F, et al. Nomenclature for secreted regulatory proteins of the immune system (interleukins). Clin Exp Immunol. 1992;88(2):367. doi:10.1111/j.1365-2249.1992.tb03089.x

26.Lagna G, Hata A, Hemmati-Brivanlou A, Massague J. Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways. Nature. 1996;383(6603):832-836. doi:10.1038/383832a0

27.Robinson J, Halliwell JA, Hayhurst JD, Flicek P, Parham P, Marsh SG. The IPD and IMGT/HLA database: allele variant databases. Nucl Acids Res. 2015;43(database issue):D423-D431. doi:10.1098/nar/gku1161

28.Bodmer WF, Albert E, Bodmer JG, et al. Nomenclature for factors of the HLA system, 1987. Hum Immunol. 1989;26(1):3-14.

29.Mickelson E. A brief history of the International Histocompatibility Workshops. Accessed May 16, 2018. https://ihiws.org/workshop-history/

30.Bodmer WF. HLA 1991. In: Tsuji K, Aizawa M, Sasazuki S, eds. HLA 1991: Proceedings of the Eleventh International Histocompatibility Workshop and Conference Held in Yokohama, Japan, 6-13 November, 1991. Oxford University Press; 1992:7-16.

31.Marsh SGE. Nomenclature for factors of the HLA system, update June 2017. Int J Immunogenet. 2017;44(5):243-250. doi:10.1111/iji.12331

32.Bodmer JG. Nomenclature 1991 foreword. Hum Immunol. 1992;34(1):2-3. doi:10.1016/0198-8859(92)90078-2

33.Marsh SGE. Nomenclature for factors of the HLA system. Updated April 4, 2017. Accessed January 30, 2018. http://hla.alleles.org/nomenclature/index.html

34.Tiercy J-M, Marsh SGE, Schreuder GMT, Albert E, Fischer G, Wassmuth R. Guidelines for nomenclature usage in HLA reports: ambiguities and conversion to serotypes. Eur J Immunogenet. 2002;29(3):273-274. doi:10.1046/j.1365-2370.2002.00336.x

35.Klein J, Bontrop RE, Dawkins RL, et al. Nomenclature for the major histocompatibility complexes of different species: a proposal. Immunogenetics. 1990;31(4):217-219. doi:10.1007/BF00204890

36.Haynes BF, Soderberg KA, Fauci AS. Introduction to the immune system. In: Longo DL, Kasper DL, Jameson JL, Fauci AS, Hauser SL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. McGraw-Hill; 2012:2650-2685.

37.Schroeder HW Jr, Wald D, Greenspan NS. Immunoglobulins: structure and function. In: Paul WE, ed. Fundamental Immunology. 7th ed. Lippincott Williams & Wilkins; 2013:129-149.

38.Nairn R, Helbert M. Immunology for Medical Students. 2nd ed. Mosby; 2007.

39.Lefranc M-P, Lefranc G. The Immunoglobulin FactsBook. Academic Press; 2001.

40.Parslow TG. Immunoglobulins and immunoglobulin genes. In: Parslow TG, Stites DP, Terr AI, Imboden JB, eds. Medical Immunology. 10th ed. Lange Medical Books/McGraw-Hill; 2001:95-114.

41.Kao NL. How immunoglobulins were named. Ann Intern Med. 1992;117(5):445. doi:10.7326/0003-4819-117-5-445_2

42.Black CA. A brief history of the discovery of the immunoglobulins and the origin of the modern immunoglobulin nomenclature. Immunol Cell Biol. 1997;75(1):65-68. doi:10.1038/icb.1997.10

43.Recommendations for the nomenclature of human immunoglobulins. Biochemistry. 1972;11(18):3311-3312. doi:10.1021/bi00768a001

44.IUIS/WHO Subcommittee on IgA Nomenclature. Nomenclature of immunoglobulin A and other proteins of the mucosal immune system. J Immunol Methods. 1999;223(2):263-264. Also: Eur J Immunol. 1999;29(3):1057-1058.

45.IUIS Subcommittee on Nomenclature. Nomenclature of the Fc receptors. Bull World Health Organ. 1989;67(4):449-450.

46.Lefranc M-P, Giudicelli V, Duroux P, et al. IMGT, the International ImMunoGeneTics Information System 25 years on. Nucl Acids Res. 2015;43(D1):D413-D422. doi:10.1093/nar/gku1056

47.Parslow TG. Lymphocytes and lymphoid tissues. In: Parslow TG, Stites DP, Terr AI, Imboden JB, eds. Medical Immunology. 10th ed. Lange Medical Books/McGraw-Hill; 2001:40-60.

48.DeFranco AL. B-cell development and the humoral immune response. In: Parslow TG, Stites DP, Terr AI, Imboden JB, eds. Medical Immunology. 10th ed. Lange Medical Books/McGraw-Hill; 2001:115-130.

49.Imboden JB, Seaman WE. T lymphocytes and natural killer cells. In: Parslow TG, Stites DP, Terr AI, Imboden JB, eds. Medical Immunology. 10th ed. Lange Medical Books/McGraw-Hill; 2001:131-147.

50.LeFranc M-P, LeFranc G. The T Cell Receptor FactsBook. Academic Press; 2001.