MOLECULAR BASIS OF INFLAMMATION AS IMMUNE

RESPONSE

)ASSINMENT # 01 SEMESTER SPRING-2019(

Submission Date (February 14, 2019)

BY

SULEMAN HUSSAIN SHAH

ROLL # 19046114-004

Zoo-703 (Molecular Immunology)

PhD Zoology and Session 2019-21

Dr Razia Iqbal
Department of Zoology

UNIVERSITY OF GUJRAT
1. Introduction

Inflammation participates importantly in host defenses against infectious agents and

injury, but it also contributes to the pathophysiology of many chronic diseases. Interactions
of cells in the innate immune system, adaptive immune system, and inflammatory
mediators orchestrate aspects of the acute and chronic inflammation that underlie diseases
of many organs. A coordinated series of common effector mechanisms of inflammation
contribute to tissue injury, oxidative stress, remodeling of the extracellular matrix,
angiogenesis, and fibrosis in diverse target tissues. Atherosclerosis provides an example of
a chronic disease that involves inflammatory mechanisms. Recruitment of blood
leukocytes characterizes the initiation of this disease. Its progression involves many
inflammatory mediators, modulated by cells of both innate and adaptive immunity. The
complications of established atheroma, including plaque disruption and thrombosis, also
intimately involve inflammation. Mastery of the inflammatory response should aid the
development of novel strategies to predict disease susceptibility, target and monitor
therapies, and ultimately develop new approaches to the prevention and treatment of
chronic diseases associated with aging, such as atherosclerosis (Schonbeck, Mach &
Sukhova, 2000).

The recognition of inflammation dates back to antiquity. As documented by Celsus in the

1st century AD, the ancients understood that the tissue response to injury gave rise to rubor
(redness, due to hyperemia), tumor (swelling, caused by increased permeability of the mi-
crovasculature and leakage of protein into the interstitial space), calor (heat, associated
with the increased blood flow and the metabolic activity of the cellular mediators of
inflammation), and dolor (pain, in part due to changes in the perivasculature and associated
nerve endings). Functio laesa (dysfunction of the organs involved) joined as a fifth
characteristic of inflammation in the writings of Rudolf Virchow in the 1850s. In the late
19th century, Elie Metchnikoff introduced the concept of phagocytosis, a fundamental
aspect of innate immunity, after watching protozoa engulf particulate matter and
examining blood leukocytes ingest foreign bodies. In 1908, the Nobel Prize for Physiology
of Medicine was jointly awarded to Metchnikoff for this discovery and to Paul Ehrlich for
his work on humoral immunity, a key component of adaptive immunity (Yao et al., 1995).

The aging of the population, the conquest of many communicable diseases, and changing
lifestyles present an epidemic of chronic disease projected to soon extend worldwide.
Inflammation provides a unifying pathophysiological mechanism underlying many chronic
diseases, including diabetes, cardiovascular disease, certain cancers and bowel diseases,
 arthritides, and osteoporosis. Common pathophysiologic scenarios apply to many of these
diseases (Schonbeck, Mach & Sukhova, 2000).
2. Need and Significance of the Topic

Emerging laboratory and clinical data provide strong evidence that inflammatory pathways
contribute decisively to the pathogenesis of a number of chronic dis-eases associated with
aging, and that these processes involve common pro-inflammatory mediators and
regulatory pathways. By understanding the common mechanisms, and shared mechanisms
that or chestrate the array of dysfunction of our various organ systems, we will be able to
better predict susceptibility to disease and gauge target therapies. Fortunately, lifestyle
measures such as abstinence from tobacco, a healthy diet, and regular physical activity can
often permit an individual to stave off many of these inflammatory concomitants of aging,
and lessen the likelihood that chronic diseases will limit a long and healthy life.
3. Review of Literature

The innate immune response mounts a rapid response to injury. It detects a broad range of
molecular patterns that are commonly found on pathogens but are foreign to mammals,
called pathogen-associated molecular patterns (PAMPs), and thus lacks the exquisite
structural specificity of recognition by the adaptive immune response. Macrophages
express a set of pattern recognition receptors including various scavenger receptors and
Toll-like receptors, whose ligands include PAMPs such as lipopolysaccharides, surface
phosphatidylserine, and aldehyde-derivatized proteins, as well as modified forms of a
classical risk factor for atherosclerosis, low-density lipoproteins (LDL) modified by
oxidation or glycation (Brown & Goldstein, 1983).

Ligation of scavenger receptors can lead to endocytosis and lysosomal degradation of the
bound ligands while engagement of Toll-like receptors results in activation of nuclear
factor-kappa B (NF- B) and mitogen-activated protein kinase (MAPK) pathways (Brown
& Goldstein, 1983). Ligation of Toll-like receptors can also heighten phagocytosis,
production of reactive oxygen species, and release of cytokines, autacoids, and lipid
mediators that coordinate and amplify the local inflammatory response (Hansson, Libby,
Schonbeck & Yan, 2002).

The other major limb of host defenses, the adaptive immune response, mounts more
slowly, and furnishes a more finely focused response mechanism that requires the
recognition of specific molecular structures and de-pends on the generation of large
numbers of antigen receptors, i.e., T-cell receptors and immunoglobulins, by somatic
rearrangement processes in blast cells (Jaffer, Libby & Weissleder, 2006). When T-cells
recognize a foreign antigen presented to them. They initiate responses that target precisely
that antigen, including a direct attack against the antigen-bearing cell by cytotoxic T-cells,
stimulation of antibody production by B-cells, and induction of a local inflammatory
response. T-cells can differentiate into at least two sub-types of T helper (Th) cells
(Kranzhofer et al., 1999); (Schonbeck, Mach & Sukhova, 2000).

Th1 cells elaborate a number of cytokines; among them, interferon gamma (IFN-g)
prominently coordinates crosstalk between innate and adaptive limbs of the immune and
inflammatory responses by stimulating the macrophage to increase its production of a
broad gamut of mediators including autacoids, reactive oxygen species, lipid species, and
pro-inflammatory cytokines. Th2 cells can stimulate humoral immunity by elaborating a
number of cytokines that stimulate B-cell maturation into antibody-producing plasma cells
and promote B-cell class-switching to increase production of immunoglobin E (IgE)
antibodies. Th2 cells can also aid recruitment and activation of mast cells, another effector
of allergic responses and contributor to chronic inflammation in a variety of tissues and
disease states. In addition to these specialized pro-inflammatory responses, Th2 cells can
dampen the inflammatory response by elaborating cytokines with anti-inflammatory
properties such as interleukin-10 (IL-10) (Libby & Theroux, 2005).

Traditionally, various subspecialties have claimed the chronic diseases of various organ
systems as their own, and probed the pathophysiology in a reductionist manner. Yet, from
a synoptic perspective, many such diseases have more mechanisms in common than
usually recognized or acknowledged. Indeed, a generic model of chronic inflammatory
disease is proposed that highlights these shared pathophysiologic mechanisms. According
to this scheme, signals from the innate and adaptive immune systems interact and converge
on two prototypic cell types: an epithelial cell and a mesenchymal cell of the affected
organs. These signals orchestrate a repertoire of tissue responses such as recruitment of
leukocytes involved in chronic inflammation, extracellular matrix remodeling, cellular
proliferation or death, and angiogenesis (Libby et al., 1986).

While diseases such as atherosclerosis, rheumatoid arthritis, cirrhosis, or interstitial lung

disease may manifest in very different ways, the same fundamental mechanisms and
mediators drive the disease process (Mach et al., 1997); (Schonbeck, Mach & Sukhova,
2000).

Helper T-cells abound in the lesions of chronic inflammation in many organs, including
atherosclerotic plaques, rheumatoid synovium, and forms of the chronic hepatitis’s, and in
a number of pulmonary diseases. The mononuclear phagocyte, cloaked variously as a foam
cell, osteoclast, histiocyte, microglia, or alveolar macrophage, also characteristically
 populates such lesions. The epithelial cell involved depends on the specific tissue involved
the vascular endothelial cell in atherosclerosis, the enterocyte in inflammatory bowel
disease, and the glomerular or tubular epithelial cell in renal disease. Similarly,
inflammatory and immune mechanisms involve different types of mesenchymal cells
depending on the organ arterial smooth muscle cells, fibroblasts, myofibroblasts,
mesangial cells, synoviocytes, or pericytes (Mallat, Corbaz & Scoazec (2001).
4. Conclusions and Recommendations

Emerging laboratory and clinical data provide strong evidence that inflammatory pathways
contribute decisively to the pathogenesis of a number of chronic dis-eases associated with
aging, and that these processes involve common pro-inflammatory mediators and
regulatory pathways. In atherosclerosis, increasing evidence points to the importance of
inflammatory processes in the recruitment and activation of leukocytes and in endothelial
dysfunction, in the progression of the disease, and ultimately in the thrombotic
complication that very often limits living well to age 100. We recognize increasingly that
many chronic diseases involve inappropriate deployment of host defenses critical to
survival of the species by favoring survival to reproductive age, but too often inimical to
individual longevity. By understanding the common mechanisms, and shared mechanisms
that or chest rate the array of dysfunction of our various organ systems, we will be able to
better predict susceptibility to disease and gauge target therapies. Fortunately, lifestyle
measures such as abstinence from tobacco, a healthy diet, and regular physical activity can
often permit an individual to stave off many of these inflammatory concomitants of aging,
and lessen the likelihood that chronic diseases will limit a long and healthy life
(Kranzhofer et al., 1999).
5. REFERENCES

Brown, M. S., & Goldstein, J. L. (1983). Lipoprotein metabolism in the macrophage:

implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem., 52,
223- 261.

Hansson, G. K., Libby, P., Schonbeck, U., & Yan, Z. Q. (2002). Innate and adaptive
immunity in the pathogenesis of ath-erosclerosis. Circ Res., 91, 281-291.

Jaffer, F.A., Libby, P., & Weissleder, R. (2006). Molecular and cellular imaging of
atherosclerosis: emerging applications. J Am Coll Cardiol., 47:1328-1338.

Kranzhofer, R., Schmidt, J., Pfeiffer, C. A., Hagl, S., Libby, P., & Kubler, W. (1999).
Angiotensin induces inflammatory activation of human vascular smooth muscle cells.
Arterioscler Thromb Vasc Biol., 19:1623-1629.

Libby, P., & Theroux, P. (2005). Pathophysiology of coronary artery disease. Circulation,
111, 3481-3488.
Libby, P., Ordovas, J. M., Auger K. R., Robbins, A. H., Birinyi, L.K., Dinarello, C.A.
(1986). Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in
adult human vascular endothelial cells. Am J Pathol., 124, 179-185.

Mach, F., Schonbeck, U., Bonnefoy, J. Y., Pober, J. S., & Libby, P. (1997). Activation of
monocyte/macrophage func-tions related to acute atheroma complication by ligation
of CD40: induction of collagenase, strome-lysin, and tissue factor. Circulation, 96, 396-
399.

Mallat, Z., Corbaz, A., & Scoazec, A. (2001). Expression of interleukin-18 in human
atherosclerotic plaques and relation to plaque instability. Circulation, 104, 1598-
1603.

Miller, D.T., Ridker, P.M., Libby, P., & Kwiatkowski, D.J. (2007). Atherosclerosis: the
path from genomics to thera-peutics. J Am Coll Cardiol., 49:1589-1599.

Ridker, P.M. (2016). C-reactive protein and the prediction of cardiovascular events among
those at intermediate risk: moving an inflammatory hypothesis toward consensus. J
Am Coll Cardiol., 49, 2129 -2138.

Rolfe, B. E., Muddiman, J. D., Smith, N. J., Campbell, G. R., Campbell, J. H. (2000).
ICAM- 1 expression by vascular smooth muscle cells is phenotype-dependent. Ath-
erosclerosis, 149, 99-110.
 Turnitin Originality Report
Tested on Feb 09, 2019, by Turnitin Anti Plagiarism Software provided by Higher Education
Commission, Pakistan to the Instructors of the University of Gujrat, Punjab, Pakistan.

Thesis Title: Molecular Basis of Inflammation as Immune Response

Authors’ Name: Suleman Hussain Shah
Institution: Department of Zoology, Faculty of Science, University of Gujrat,
Gujrat, Pakistan.

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