The Origin of Chronic Inflammatory Systemic Diseases and their Sequelae

Rainer Straub

• Publisher: Academic Press
• Year: 2015
• ISBN:
  9780128033227
• Topic: Medizin
• Subtopic: Immunologie

Chronic inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, inflammatory bowel diseases, and others typically stimulate a systemic response of the entire body. This response has a uniform character in many diseases because common pathways are switched on. The uniform response regulates systemic energy and water provision. However, long-term application of this program leads to typical disease sequelae such as fatigue / depressive symptoms, sleep disturbances, anorexia, malnutrition, muscle wasting – cachexia, cachectic obesity, insulin resistance, dyslipidemia, alterations of steroid hormone axes, disturbances of the hypothalamic-pituitary-gonadal axis, elevated sympathetic tone, hypertension, volume expansion, decreased parasympathetic tone, inflammation–related anemia, bone loss, hypercoagulability, circadian rhythms of symptoms, and disease exacerbation by stress.

The Origin of Chronic Inflammatory Systemic Diseases and Their Sequelae demonstrates concepts of neuroendocrine immunology, energy and water regulation, and evolutionary medicine in order to show that the uniform response that regulates systemic energy and water provision, has been positively selected for acute physiological responses and short-lived disease states, but is a misguided program in chronic inflammatory diseases and aging.

• Offers a broad conceptual framework with a strong clinical link, written in an easy to grasp style and demonstrating the link to aging research
• Describes the important principles derived from basic immunology that are used to explain pathogenesis of chronic inflammatory systemic diseases with a focus on autoimmunity
• Defines the bioenergetics and energy regulation of the body explaining common response pathways typical for systemic inflammation
• Makes use of evolutionary medicine theory to demonstrate the uniformity of the systemic response
• Explains the appearance of typical disease sequelae on the basis of the three pillars: neuroendocrine immunology, energy regulation, and evolutionary medicine theory
• Contains color figures and tables that explain the field to newcomers

Chapter I

History of Immunology Research

Abstract

The new concepts described in this book have their solid footing in immunological research over the last 150 years. In order to give the reader a short overview on the most important immunological principles, this chapter summarizes the development of immunological research in a compact form. The first part of the chapter recapitulates principles from basic immunology beginning in the nineteenth century and ending with epigenetics and microRNA in the 2000s. The second part adds pathogenic effector mechanisms relevant to chronic inflammatory systemic diseases. It is a specific elaboration on principles that lead to autoimmunity and proinflammatory effector functions. The third part of this chapter examines triggering mechanisms that start chronic inflammatory systemic diseases, and the last part discusses the timescale of these diseases. The timescale considers the asymptomatic and symptomatic phases of chronic inflammatory systemic diseases, but it also recognizes an important priming phase in utero. With this preceding information, the reader should be prepared for the new elements discussed in the book.

Keywords

Basic immunology

Pathophysiology

Chronic inflammatory diseases

Autoimmunity

Inflammation

Inflammatory trigger

Chapter Contents

Before 1945: The Early Days 2

1945-1960: Immunology Reawakens 3

1960-Today: Pure Immunology 5

Summary 16

Pathogenic Effector Mechanisms of Chronic Inflammatory Systemic Diseases 18

Autoantibody, Immune Complex, and Complement 20

B Cells and Plasma Cells 22

T Cells 23

MHC and Immunogenetics 26

Monocytes and Macrophages 29

Dendritic Cells 31

NK Cells 32

Neutrophils 33

Apoptosis 34

Adhesion and Costimulatory Molecules, Vascular Transmigration, and Chemokines 35

Pattern Recognition Receptors 36

The Local Cellular Support System of Inflammation 37

Fibroblasts and Astrocytes 37

Stromal Cells of the Bone Marrow 38

Endothelial Cells, Mesangial Cells, and Neovascularization 38

Epithelial Cells 38

Keratinocytes 39

Oligodendrocytes 40

Adipocytes 40

Myocytes 41

Eosinophils, Basophils, and Mast Cells 41

Signaling Pathways: Genome-Wide Association Studies 41

The Trigger of Chronic Inflammatory Systemic Diseases 46

The Timescale 51

The Asymptomatic Phase of Chronic Inflammatory Systemic Diseases 51

The Symptomatic Phase of Chronic Inflammatory Systemic Diseases 54

The Plasticity Phase of Chronic Inflammatory Systemic Diseases in Early Life 55

Summary 56

In order to position the new theory presented in this book relative to present explanatory models in the field of immunology, an historic outline of important achievements in immunology and immunological paradigms relevant to the etiology of chronic inflammatory systemic diseases is given. It is not the idea to present a complete history of immunology or autoimmunity because this has already been done by merited scholars⁵ and others in many reviews cited below. The achievements are summed up in Table 1 at the end of the collection in “Summary” section.

Table 1

Major Achievements in Immunology

What	Who	When
Variolation	Timoni, Sloane, and Jenner	Eighteenth century
Bacteriology and link to immunology	Pasteur, Koch, and others	1880s
Phagocytes (monocytes, macrophages, neutrophils)	Metchnikoff	1880s
Antitoxic antibodies, passive transfer	Behring, Kitasato	1890s
Antibodies, B cell receptor, basophils, mast cells, eosinophils	Ehrlich	1897
Complement and fixation	Buchner, Bordet and Gengou	1880-1900
Allergic reactions, hypersensitivity	Richet, Bordet, Pirquet, Arthus	About 1900
First autoimmune disease	Donath and Landsteiner	1904
Blood group antigens	Landsteiner	1900
Immunochemistry	Arrhenius	1907
MNP blood group antigens, Rh blood group system	Landsteiner	1926, 1940
Histocompatibility complex	Snell and Gorer, Dausset	1945-1965
Histocompatibility complex has immune function	Benacerraf, McDevitt	1960s
Principles in transplantation and acquired specific tolerance	Medawar	1945-1955
Immunodeficiency disease	Bruton	1952
Clonal selection theory; self versus nonself	Burnet, Talmage, Lederberg	Late 1950s
Radioimmunoassay	Yalow and Berson	1960
Immunoglobulin structure	Porter, Edelman	1960s
Hypervariable complementarity-determining residues (CDR)	Wu and Kabat	1970
Immunoglobulin gene and somatic rearrangement of Ig genes	Hozumi, Tonegawa	1976
Different lymphocytes (B and T)	Many (Mitchell, Miller, Claman)	1960s
T helper cells	Many	1960s
T suppressor cells	Gershon, Benacerraf and Katz	Late 1960s
Cytotoxic cells	Cerottini, Janeway	Early 1970s
First T cell surface molecule (Thy-1)	Raff	1969
Class switch recombination of immunoglobulins	Kincade	Early 1970s
Antigen presentation within the MHC-encoded protein	Shevach, Rosenthal, Katz, Kindred, Shreffler	Early 1970s
MHC class I—restriction of cytotoxic T cell recognition, self versus altered self	Zinkernagel and Doherty	1970s
Fluorescence-activated cell sorting	Herzenberg	Early 1970s
Monoclonal antibodies	Köhler and Milstein	1976
MHC-encoded protein structure and function	Many	1980s
Immunogenetics, HLA as a risk factor	Many	1970-1990
Dendritic cells	Steinman and Cohn	1993
T cell receptor	Many	1984
Natural killer cell, missing self	Lanier, Kärre, Yokoyama	1986
Cytokines, growth factors	Innumerable many	1950+
Th1/Th2 paradigm	Mosmann	1986
Th17 paradigm	Many	Late 1990s
Apoptosis mechanisms	Kerr, Wyllie, and Currie; many	1972+
Lymphocyte lineage transcription factors	Many	Late 1980s
Recombination-activating genes 1/2 (RAG-1/2)	Baltimore	Late 1980s
Adhesion and costimulatory molecules	Many (Springer, Kishimoto)	1980s
Vascular transmigration	Many	1980s
Chemokines	Many	Late 1980s
Migration and homing of lymphocytes	Many (Gowans)	1920s+
The memory of the immune response	Many	1900+
Pattern recognition receptors, noninfectious self versus infectious nonself	Janeway, Beutler, Hoffmann; many	1990s
Danger theory	Matzinger	1990s
Central tolerance in the thymus	Miller, many others	1961, 1985+
Regulatory T cells (successors of T suppressor cells), CD25, CD4, Foxp3	Sakaguchi	1990s
Signal transduction in immune cells	Many	1960s+
Epigenetics	Many	1950s+
MicroRNA	Tuschl, Ambros, Bartel	2000s

Before 1945: The Early Days

The history of modern immunology as a mature science started with the outstanding accomplishments of Louis Pasteur, Robert Koch, Emil von Behring and Shibasaburo Kitasato, Élie Metchnikoff, Charles Richet, Jules Bordet, and others in the field of bacteriology and immunology, a time often called the golden age of immunology (this is not to forget the variolation studies of Timoni, Sloane, or Jenner the century before). These golden age immunologists developed the concept of humoral immunity (antibodies and complement) and cellular immunity (phagocytes: macrophages and microphages (neutrophils)). While the German school favored the humoral aspect, the French/Russian school favored the cellular aspect, which appeared to be a significant conflict between the two groups (probably also stimulated by the war conflicts of the nineteenth century between France and Germany).

Although the cellular phagocyte theory of Metchnikoff was respected as a general biological phenomenon in the early twentieth century, most scientists started doing work on antibodies and complement rather than on cells.⁵ Arthur Silverstein named this phenomenon “the growing humoral tide.” For a period of almost 50 years, cells did not play a ro...