Human Immunogenetics

Basic Principles and Clinical Relevance

S. D. Litwin

• Publisher: CRC Press
• Year: 2020
• Print ISBN: 9780824778996
• eBook ISBN: 9781000147162
• Topic: Medicine
• Subtopic: Diseases & Allergies

Delineating fundamental concepts of contemporary immunogenetics, this reference/text examines specific immunogenetic systems in terms of molecular biochemistry and immunophysiology. Covers material in diverse fields, including infectious diseases, cell biology, virology, molecular genetics. Comprise

Part I
Approaches and Tools of Immunogenetics

Introduction

The goal of this section is to outline the ways in which immunogenetic information is gathered and evaluated and “prepare the ground,” so to speak, for the specific systems detailed in Parts II through V.

The leadoff chapter on acquisition of genetic information reviews avenues of approach including that of cell surface immunogenetics, an area that has received strong impetus from the widening utilization of monoclonal antibodies and cloning-immortalization of immune cells and has proved critically useful in studying cell differentiation and tumor-associated antigens. Additional insights into “acquiring” genetic data are available from Dr. Winn’s Laws of Transplantation (Chap. 3), Dr. Sparkes’ Human Gene Mapping and Linkage Analysis (Chap. 2), and Dr. Pollok’s discussion of molecular genetics (Chap. 5). In addition, Dr. Ross and co-workers review applications for monoclonal antibodies and provide a view of an illustrative tumor-associated antigen (Chap. 6).

Certain biologic problems and disease groups are closely associated with immunogenetic approaches and principles. These include the maternal-fetal relationship, transplantation of tissues, and transfusion of blood, as well as autoimmune and immunodeficiency diseases. Dr. Mogil and Dr. Wegmann’s chapter on Maternal-Fetal Immunogenetics (Chap. 4), and Dr. Winn’s on the Laws of Transplantation each provide a careful current view of these issues while autoimmunity (see Chap. 12), immunodeficiency disease (Chap. 13), and transfusion issues (touched on in Chaps. 28–31) are dealt with as part of other sections.

Stephen D. Litwin

1
Acquiring Immunogenetic Data

Stephen D. Litwin^* / Guthrie Research Institute, Guthrie Foundation for Medical Research, Sayre, Pennsylvania

* Present affiliation: Veterans Administration Central Office, Washington, D.C.

I. Immunologic Recognition

A. The immune response recognizes subtle chemical differences: Landsteiner’s contributions

B. Fidelity and specificity of immune recognition

C. Fundamental considerations in antigenicity and immunogenicity

D. Terminology permits classification of genetic and species differences between responder and source of antigen

E. Genetic typing

F. Antigen recognition and processing differs in ant ibo dy-mediated and cell-mediated immunity

II. Cell Surface Immunogenetics

A. Immunogenetics

B. Technical considerations

C. Tumor-associated antigens

III. Genetically Defined Animals

A. Inbreeding

B. Coisogenic and congenic lines

C. Recombinant-inbred strains

D. Outbred species

IV. Immunogenetic Analysis

A. Mendel’s laws of inheritance provide the basic approach to genetic analysis

B. Complexities in using antigen expression to monitor gene expression 27

C. Allelic genes hard to distinguish from closely linked genes

D. Nomenclature

E. Population genetics of immunogenetic markers

F. Segregation and pedigree analysis

References

I. IMMUNOLOGIC RECOGNITION

A. The Immune Response Recognizes Subtle Chemical Differences: Landsteiner’s Contributions

Karl Landsteiner, in a close to 50-year laboratory career (1897–1943), applied a chemist’s perspective to analysis of the specificity of the immune response. A historical recapitulation of his basic experiments is provided in a Dover Press 1962 reprint of the volume, The Specificity of the Serological Reactions (1).

Certain definitions from this work remain as useful today as when initially proposed. “Substances inciting the formation of and reacting with antibodies are named antigens.” “Sera that contain antibodies as a result of the injection of antigens are immune sera (antisera)”; the designation of “normal” or “natural antibodies” is applied to substances, found in the serum of untreated animals, that are similar in their effects to the antibodies developed by immunization (1).

Landsteiner’s preoccupation was, in his own words, “…the phenomenon of serologic specificity, not yet fully explained” (author’s preface to Ref. 1). He explored these problems by employing proteins of relatively simple structure and low molecular weight (haptens). Antigenicity, which is the ability to bind to antibody, was retained by haptens, whereas the more complex property of immunogenicity, which is the ability to elicit an immune response, was absent unless haptens were associated with a carrier protein. Antigenicity and immunogenicity could thus be dissociated. This single seminal observation prematurely alerted scientists to the presence of host antigen processing and host regulatory factors of key importance.

A second preoccupation of Land steiner was to view immune phenomena as chemical reactions. The term immunochemistry was to come into more general use through the efforts of a second and third generation of immunochemists. These cumulative efforts propelled immunology into the area of modern sciences today interacting closely with genetics, cell biology, virology, oncology, micro-biology, and others. The second major inheritance from Landsteiner is then his view of immunology as a “hard” science and ranks with his lifelong curiosity about the nature of immune cognition.

B. Fidelity and Specificity of Immune Recognition

The high fidelity and exquisite sensitivity of immune recognition to nuances of chemical structure and configuration was apparent in initial hapten studies illustrated in Table 1. These turn-of-the-century experiments by Landsteiner relied on either direct hemagglutination of chemically coated red cells or immune precipitation as an endpoint (1): the conclusions reached have been repeatedly confirmed in more recent complex assays. Table 1A demonstrates that immune antisera can distinguish between different chemical structures, whereas Table 1B carries recognition a step further. Related haptens differing by one amino acid are recognized as immunologically distinct. In Table 1C the three steric forms of tartaric acid, identical with each other in primary structure but spatially different, provoke immune antisera that “see” differences. In summary, there is convincing evidence that antibody-mediated immune recognition can easily distinguish amino acid or monosaccharide residue differences and can discern different molecular spatial patterns to the degree that even moderate degrees of protein denaturation, the steric derangements during antibody-antigen complexing, or receptor-ligand interactions can be detected. In view of these data it is not surprising that genetic variations, as limited as a single amino acid replacement or addition of a terminal sugar, can be detected immunologically.

Table 1 Specificity of Immune Antisera Tested with Haptens^a

	Immune antisera against	Test antigens
p-Aminobenzoic acid		p-Aminophenyl-acid	Aniline	p-Toluidine
A	p-Aminobenzoic acid	+++	±	0	0
	p-Ammophenyl-arsenic acid	0	++++	0	NT
	Aniline	0	0	++±	+
	p-Toluidine	0	0	++	++±
		Glycyl-Glycine	Glycyl-Leucine	Leucyl-Leu cine
B	Glycyl-glycine	++±	0	0
	Glycyl-leucine	0	++±	0
	Leucyl-leucine	0	+	++
		l-Tartaric acid	d-Tarlaric acid	m-Tartaric acid
C	l-Tartaric acid	+++++ ±	+ 0	+ +
	d-Tartaric acid	0 0	+++ ++ ±	+ +
	m-Tartaric acid	+ +	0 0	+++ +++

a Testing was by agglutination of antigen-coated red cells. Reactions were graded from no reaction (0) to complete agglutination (++++). NT is not tested.

Source: Data from K. Landsteiner, Specificity of Serologic Reactions. Dover Press p. 168 (1A), p. 173 (IB), and p 178 (1C).

C. Fundamental Considerations in Antigenicity and Immunogenicity

There are certain fundamental determinants of antigenicity and immunogenicity that apply to all epitopes, regardless of whether or not they are genetic. These considerations start with the primary structure of the epitope, i.e., the amino acid and carbohydrate sequences, and go on to include steric-spatial or tertiary configuration, the positioning of the epitope with respect to the outer as opposed to the inner regions of the molecule, epitope hydrophobicity or hydro-philicity, electrical charge, segmental mobility, and other properties. Several excellent reviews of antigenicity are available (2–4).

Host factors are particularly critical because immunogenicity can be defined only as presented in a given host. The degree of host factor participation and its mechanisms are a point of contention between experimental camps which view antigenicity using different theoretical constructs. One widely accepted major host factor, however, is immunological distance or the number of amino acid differences between a host’s and the antigens’ homologous proteins. Immunologic distance depends on evolutionary distance and correlates well with immunologic cross-reactivity as illustrated in Table 2. Immunologic cross-reactivity however, does not parallel the fine specificity of immune cognition. The latter is the detection of subtle antigenic distinctions, including genetic ones, and is often easier to elicit when responder and antigen species are closely related.

Table 2 Correlation Between Amino Acid Species Differences and Immunological Distance

Protein	Correlation coefficient^a
Lysozyme	0.95
Ribonuclease	0.92
Myoglobin	0.87
Cytochrome c	0.87
Azurin	0.85
Albumin	0.96

a Rabbits were immunized with each protein and the group of evolutionarily related proteins were tested for immuno-logic cross-reactivity using...

Table of contents

• Cover
• Half Title
• Series Page
• Title Page
• Copyright Page
• Series Introduction
• Foreword
• Preface
• Contents
• Contributors
• Part I. Approaches and Tools of Immunogenetics
• Part II. Immunogenetics of Immunity
• Part II. Immunogenetics of Histocompatibility and Related Systems
• Part IV. Immunogenetics of Tumor and Viral Antigens
• Part V. Immunogenetics of Blood and Serum Components
• Index