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):

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

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

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:

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.

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:

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

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

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 nomenclature^24,25 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)

 β_c-utilizing (common cytokine receptor β chain)

 γ_c-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

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:

14.8.4.4 Hormones.

These hormones are also considered cytokines:

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:

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

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:

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: α_1, α_2, 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:

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

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:

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:

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:

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

^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,

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.

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:

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):

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

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:

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

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

Light chains have 1 variable (V_L) and 1 constant (C_L) domain.

14.8.6.1 Immunoglobulin Antigen-Binding Site.

The V_H and the V_L 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:

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:

14.8.6.2 Immunoglobulin Constant Regions

The C_H and C_L 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 C_H 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.

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 (C_H). 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 serum^41,42:

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

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

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):

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:

C_L and V_L regions may be specified by light chain type, as follows:

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

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:

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):

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:

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):

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:

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

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):

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:

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):

V_κ3⁺

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

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

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.

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):

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:

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

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:

The theoretical helper T precursor to these subtypes is abbreviated:

T_Hp

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:

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

There are 2 subtypes of the γ chain:

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:

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

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

V_β2⁺

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:

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:

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.

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