The document discusses mechanisms of autoimmune disease. It begins by explaining that autoimmune disease occurs when the immune system attacks the body's own tissues. It then discusses several factors that can contribute to autoimmune diseases, including genetics, environment, hormones, diet, toxins/drugs, and infections. Common mechanisms by which autoimmune diseases develop include antibody-mediated damage and cell-mediated damage through immune cells like T cells and macrophages.
The term Autoimmunity is coined by Paul Enrlich.
Autoimmunity is defined as humoral or cell mediated immune response against self antigens
Autoimmune diseases are a group of disorders caused by immune response to self antigens.
Autoimmune DIseases : Types, Mechanism, Diagnosis, TreatmentDr Mehul Dave
This is a presentation useful to learners of immunology as well as acadeicians. Useful in undergraduate as well as postgraduate courses. NEET students/Teachers can also get advantage of it.
The term Autoimmunity is coined by Paul Enrlich.
Autoimmunity is defined as humoral or cell mediated immune response against self antigens
Autoimmune diseases are a group of disorders caused by immune response to self antigens.
Autoimmune DIseases : Types, Mechanism, Diagnosis, TreatmentDr Mehul Dave
This is a presentation useful to learners of immunology as well as acadeicians. Useful in undergraduate as well as postgraduate courses. NEET students/Teachers can also get advantage of it.
Autoimmunity is the system of immune responses of an organism against its own healthy cells and tissues. Any disease that results from such an aberrant immune response is termed an "autoimmune disease".
The presentation includes an overview of hypersensitivity and type 1 hypersensitivity with certain pictures elaborating the mechanism. The presentation also talks about asthma very briefly as an example of type 1 hypersensitivity.
Autoimmunity is the system of immune responses of an organism against its own healthy cells and tissues. Any disease that results from such an aberrant immune response is termed an "autoimmune disease".
The presentation includes an overview of hypersensitivity and type 1 hypersensitivity with certain pictures elaborating the mechanism. The presentation also talks about asthma very briefly as an example of type 1 hypersensitivity.
High-Yield Internal Medicine Board Review PearlsKnowmedge
This book contains chapters covering High-Yield pearls for all major categories seen on the Internal Medicine Board Exam / Shelf Exam. The chapters were created using the ABIM Internal Medicine Board Exam Blueprint. It is relevant for anyone interested in Internal Medicine information, including those preparing for the NBME Internal Medicine Shelf Exam and the USMLE Step 3 exam.
Topics covered include Cardiovascular Disease, Endocrinology & Metabolism, Gastroenterology, General Internal Medicine, Hematology, Infectious Disease, Nephrology / Urology, Oncology, Neurology, Dermatology, Pulmonary Disease & Critical Care, Rheumatology / Orthopedics
The book also contains 2 bonus chapters on how to study for the ABIM Internal Medicine Exam and the NBME Internal Medicine Shelf Exam.
Find out why diagnosis and management of autoimmune disease can be flawed. Identify the full range of triggers of autoimmune disease. Once identified, these can give you action steps to help prevent or mitigate autoimmune disease.
Vitiligo is an acquired organ specific autoimmune disease of unknown etiology characterized by white patches in the skin. The patho-physiology of this disease is characterized by loss of functional melanocytes associated with infiltration of reactive T cells and dendritic cells. So, there are many evidences support that autoimmunity has a great role in Vitiligo-pathogenesis. Many efforts were made in areas of Histopathology, Immunology, and molecular biology to solve vitiligo puzzle. However, no clear etiology was described. We tried here to review some histopathological findings that make strong evidences for the autoimmunity in this disease.
Introduction Autoimmune Disease by Dr. Kelly CobbNouriche Medspa
The immune system represents an interface between a constant ever-changing external environment and an internal system that is striving to maintain homeostasis and defend its boundaries from harmful foreign invaders.
Microbiota, vitamin D receptor VDR and autoimmuityfathi neana
The big question is what is behind sickness during our life ?. How the pathogens can prevail and what happen to our immune system and microbiota. How the pathogens in a clever way shut down the innate immunity causing persistent chronic illness, chronic inflammation, maladaptive autoimmunity and other chronic diseases. What is the rule of vitamin D and its receptor VDR . What about the current debate regarding the best choice for managing vitamin D deficient function. Hope we can find the answer in this presentation.
Tolerance and Autoimmunity By Dr. Kanury Rao.pptxDr.Kanury Rao
The term ‘immune tolerance’ indicates the lack of response of the immune mechanism to its own antigens. The autoimmunity is caused by the breakdown of immunity tolerance. Dr. Kanury Rao is analyzing the causes and preventions of these diseases
The organism possesses powerful mechanism to avoid immune auto aggression, The acquired ability of the immune system to avoid responsiveness to self antigens is defined as ‘ tolerance’ It is obtained by the cooperative efforts of central and peripheral mechanisms, which allow a rapid and efficient removal of pathogens ( Virus and Bacteria ) in the absence of self-recognition, It is a dysfunction of the immune system. The immune system protects you from disease and infection. Sometimes, though, the immune system can produce autoantibodies that attack healthy cells, tissues, and organs. This can lead to autoimmune disease.Autoimmune diseases can affect any part of the body
Autoimmunity and Autoimmune diseases.pptxrajmonu7858
A concise ppt about autoimmunity. It incudes information about tolerance, etiology behind autoimmune diseases, types of autoimmune diseases and few examples of diseases.
Allergies, also known as allergic diseases, are a number of conditions caused by hypersensitivity of the immune system to something in the environment that usually causes little problem in most people
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
The Gram stain is a fundamental technique in microbiology used to classify bacteria based on their cell wall structure. It provides a quick and simple method to distinguish between Gram-positive and Gram-negative bacteria, which have different susceptibilities to antibiotics
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
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New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
CDSCO and Phamacovigilance {Regulatory body in India}NEHA GUPTA
The Central Drugs Standard Control Organization (CDSCO) is India's national regulatory body for pharmaceuticals and medical devices. Operating under the Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India, the CDSCO is responsible for approving new drugs, conducting clinical trials, setting standards for drugs, controlling the quality of imported drugs, and coordinating the activities of State Drug Control Organizations by providing expert advice.
Pharmacovigilance, on the other hand, is the science and activities related to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems. The primary aim of pharmacovigilance is to ensure the safety and efficacy of medicines, thereby protecting public health.
In India, pharmacovigilance activities are monitored by the Pharmacovigilance Programme of India (PvPI), which works closely with CDSCO to collect, analyze, and act upon data regarding adverse drug reactions (ADRs). Together, they play a critical role in ensuring that the benefits of drugs outweigh their risks, maintaining high standards of patient safety, and promoting the rational use of medicines.
Adv. biopharm. APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMSAkankshaAshtankar
MIP 201T & MPH 202T
ADVANCED BIOPHARMACEUTICS & PHARMACOKINETICS : UNIT 5
APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMS By - AKANKSHA ASHTANKAR
1. Autoimmune Disease:
Mechanisms
DeLisa Fairweather, Johns Hopkins University, Bloomberg School of Public Health, Baltimore,
Maryland, USA
The immune system provides protection against infectious organisms and repairs tissue
damage induced by infections or physical damage. Autoimmune disease occurs when the
immune response inflicts damage to tissues in the body.
Introduction
The immune system specifically recognizes and eliminates
foreign agents thereby protecting the host against infec-
tion. During maturation of the immune system, immune
cells that react against self-tissues are eliminated providing
an immune system that is ‘tolerant’ to self. Historically,
autoimmunity or reactivity of the immune system to
self-antigens was thought of as an aberrant response. More
recently, researchers have realized that autoimmunity is a
natural phenomenon, with self-reactive antibodies and
autoimmune cells present in all normal individuals. Anti-
self responses are usually generated in the process of
mounting an immune response to foreign antigens, but
autoimmune disease results only if autoimmunity is poorly
regulated. A combination of genetic predisposition and
environmental factors contribute to the development of
autoimmune disease. Although individual autoimmune
diseases are relatively uncommon, as a group they affect
approximately 5–8% of the population in the United
States and are the third most common category of disease
in industrialized countries following cardiovascular dis-
ease and cancer. Because many autoimmune diseases start
at a relatively young age and continue throughout life, they
have a disproportionate affect on public health with an
estimated annual cost of over 100 billion dollars in the
United States alone. Furthermore, most autoimmune
diseases are chronic in nature requiring a lifetime of care.
Understanding the mechanisms that lead to dysregulation
of the immune response resulting in autoimmune disease is
necessary to develop better therapies to treat and possibly
even prevent these diseases.
Genetics
The development of autoimmune disease depends on
a combination of genetic and environmental factors
(Figure 1). Most autoimmune diseases are thought to be
polygenic, involving more than one gene. The idea that
individuals are genetically predisposed to develop autoim-
mune disease arose from clinical reports that patients often
describe a family history of autoimmune diseases. For
example, patients with the autoimmune thyroid diseases,
Graves’ disease or Hashimoto’s thyroiditis, have a family
history of developing one or the other of these diseases.
Patients with autoimmune thyroid disease are also more
likely to develop other autoimmune diseases like systemic
lupus erythematosus (lupus), pernicious anaemia, type I
diabetes or Addison disease. There is also a higher prob-
ability that other family members without autoimmune
disease will develop increased levels of autoantibodies. The
fact that autoimmune diseases cluster in families and in
individuals suggests that common mechanisms increase
autoimmunity in genetically susceptible individuals. Thus,
defects in genes that regulate inflammation, for example,
could increase the susceptibility of developing an autoim-
mune disease. See also: Autoimmune Disease: Genetics
Human lymphocyte antigen, or HLA haplotype, is the
best available predictor of developing an autoimmune
disease. The likelihood of developing similar autoantibod-
ies relates directly to sharing HLA haplotypes with family
members and the probability is even greater if two haplo-
types rather than one are shared. HLA haplotype, or the
major histocompatibility complex (MHC) in mice, is
proposed to increase autoimmune disease by enhancing
antigen presentation in the periphery resulting in increased
T-cell activation. Genes outside of the MHC also contrib-
ute to the risk for developing autoimmune disease. Exten-
sive studies of type I diabetes mellitus and lupus or their
animal models, have revealed a number of non-MHC
genes that contribute to susceptibility. Common suscepti-
bility loci have been found for a number of different
autoimmune diseases, including diabetes and myocarditis,
suggesting that shared genes are involved in the pathogen-
esis of autoimmune diseases. Recent evidence suggests
that many of the genes conferring susceptibility control
immunoregulatory factors.
Studies of the prevalence of autoimmune disease in
monozygotic and dizygotic twins indicate that environ-
mental factors are also necessary for the development of
disease. If an autoimmune disease is due entirely to genes,
then its concordance rate in identical monozygotic twins
should be 100% and its concordance in nonidentical
Article Contents
Introductory article
. Introduction
. Genetics
. Environment
. Autoimmune Disease
. Common Mechanisms
doi: 10.1002/9780470015902.a0020193
1ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net
2. dizygotic twins 50%. However, if autoimmune disease is
due to environmental factors, the concordance rate should
be similar in monozygotic and dizygotic twins. Compar-
ison of the occurrence of autoimmune diseases in genet-
ically identical, monozygotic twins found a concordance
rate in the range of 10–50% in different studies and 2–40%
for dizygotic twins. The low disease concordance in mono-
zygotic twins (550%) indicates that environmental agents
are important in the development of autoimmune diseases.
Thus, heredity accounts for only about one-third of the
risk of developing an autoimmune disease, while nonin-
herited, environmental factors account for the remaining
70% risk (Figure 1).
Environment
External environmental factors such as hormones, diet,
drugs,toxinsand/or infectionsare importantindetermining
whether an individual will develop autoimmune disease.
Environmental agents are able to amplify autoimmunity in
genetically susceptible individuals and to break tolerance
in genetically resistant individuals, thereby increasing the
risk of developing autoimmune disease (Figure 2). See also:
Autoimmune Disease
Hormones
Most autoimmune diseases are more prevalent in women
than men. Conservative estimates indicate that nearly
80% of individuals with autoimmune diseases are women.
Exceptions include diabetes mellitus, ankylosing spondy-
litis and inflammatory heart disease, which occur more
frequently in men. Hormones are obtained from external
sources like diet (i.e. soy), drugs (i.e. birth control pills)
or skin products in addition to production of steroids by
the body. Sex hormones (natural and synthetic) directly
interact with cells of the immune system via receptors
on the surface or inside immune cells. Steroid hormones,
including oestrogens and androgens, are known to influ-
ence antibody production and immune cell proliferation.
Thus, hormones can amplify or inhibit the immune
response. Women produce elevated antibody responses
compared to men, while men often develop more severe
inflammation. Most of our understanding of sex differ-
ences and the immune response is derived from studies
conducted in animal models. Many animal models show a
sex-bias in prevalence and severity of disease that is similar
to human autoimmune diseases. Understanding how sex
hormones regulate the immune response is an area of avid
research.
Diet
Any number of environmental agents present in our diet,
such as chemical food additives or pesticides, could inter-
fere with regulation of the immune response contributing
to the development of autoimmune disease in genetically
susceptible individuals. One dietary component that has
been shown to increase autoimmune disease is iodine. The
increased prevalence of autoimmune thyroid disease in
United States and Western European populations has been
associated with increased use of iodized salt. Iodine binds
to the thyroid hormone precursor, thyroglobulin, making
it a target for the immune system resulting in increased
autoantibodies against thyroglobulin and recruitment of
inflammation to the thyroid gland.
Coeliac disease resulting from gluten-sensitivity also has
the hallmarks of an autoimmune disease. Genetically
susceptible individuals develop hypersensitivity to wheat
gluten and similar proteins of barley, rye and oats resulting
in inflammation of the intestine and autoantibodies against
the enzyme transglutaminase as well as calreticulin and
actin. Although considerable progress has been made
Genes
Environment
+
1) Increase
autoimmunity
2) Decrease
regulation of
autoimmunity
Autoimmune
disease
Figure 2 Alterations in mechanisms that regulate inflammation, whether due to genes and/or environment, contribute to the progression from
autoimmunity to autoimmune disease. Autoimmune responses are usually generated in the process of mounting an immune response to foreign antigens,
but autoimmune disease results only if autoimmunity persists and is poorly regulated.
Genes
30%
Environment
70%
Autoimmune
disease
+
Figure 1 The development of autoimmune disease depends on a combination of genetic and environmental factors like hormones, diet, toxins, drugs
and infections. Genetic predisposition accounts for only about one-third of the risk of developing an autoimmune disease, while noninherited
environmental factors account for the remaining 70% risk.
Autoimmune Disease: Mechanisms
2
3. regarding the molecular basis of coeliac disease, many
questions remain regarding its status as an autoimmune
disease. An important question is whether other autoim-
mune disorders can be initiated by immune responses to
foreign, yet unidentified, antigens.
Toxins/drugs
For quite some time, toxins like heavy metals or drugs
intended for therapy have been associated with disease
syndromes resembling autoimmune diseases. For example,
drugs like procainamide and hydralazine can induce auto-
antibodies and lupus-like disorders in patients. Penicil-
lamine has been associated with myasthenia gravis and
a-methyldopa is known to cause a form of haemolytic
anaemia. However, in all cases of drug-induced autoim-
mune diseases described thus far, the disease disappears
when the drug is removed.
Various heavy metals, such as mercury, silver or gold, can
induce an autoantibody response to cell nuclear antigens in
susceptible strains of mice. By yet unknown mechanisms,
mercurial compounds have been shown to exacerbate auto-
immune disease in experimental animal models. Recently,
administration of mercuric chloride to susceptible strains
of mice was found to increase autoantibodies and cell-
mediated autoimmunity in a collagen-induced model of
arthritis. These findings suggest that environmental factors
like the microbial component of adjuvant in the collagen-
induced model and mercury exposure can act synergistically
to promote autoimmune disease.
Infections
Bacterial and viral infections were some of the first agents
associated with autoimmune diseases more than a century
ago. However, most of the clinical evidence linking auto-
immune diseases with preceding infections is only circum-
stantial. For example, diabetes has been associated with
coxsackievirus and cytomegalovirus infections, multiple
sclerosis with Epstein–Barr virus and measles virus infec-
tions,rheumatoidarthritiswith mycobacteriaandEpstein–
Barr infections and myocarditis with coxsackievirus and
cytomegalovirus infections, to name a few. Since infections
generally occur well before the onset of signs and symp-
toms of autoimmune disease, linking a specific causative
agent to a particular autoimmune disease is difficult. The
most direct evidence that infectious agents can induce
autoimmune disease is the development of disease in exper-
imental animals following inoculation with self-antigens
in combination with adjuvant containing uninfectious
microbial antigens. The fact that multiple, diverse types of
microorganisms are associated with a single autoimmune
disease suggests that infectious agents induce autoimmune
disease through common mechanisms.
Several mechanisms have been proposed for how infec-
tions can lead to autoimmune disease including direct viral
damage, release of cryptic self-peptides, antigenic spread,
molecular mimicry, bystander activation and the adjuvant
effect. Molecular mimicry is the concept that antigens
of the microorganism closely resemble self-antigens and
so when an infection occurs autoimmunity is also induced.
Bystander activation may occur when the immune
response is nonspecifically stimulated by the infection
resulting in activation of autoimmunity in genetically
susceptible individuals. The adjuvant effect describes the
specific activation of the innate immune response by micro-
bial antigens as occurs, for example, during administration
of adjuvants in vaccines. A number of autoimmune
diseases can be induced experimentally by administering
self-antigen with adjuvant, such as rheumatoid arthritis
with collagen, multiple sclerosis with myelin basic protein
and myocarditis with cardiac myosin. Animal models of
autoimmune disease, whether induced with adjuvants or
chemicals, spontaneous as in the nonobese diabetic (NOD)
mouse or biobreeding (BB) rat models of diabetes or genet-
ically engineered models, provide valuable information on
the mechanisms leading to disease and the efficacy of ther-
apeutic strategies designed to combat autoimmune disease.
See also: Autoimmune Disease: Animal Models
Autoimmune Disease
A common feature of all autoimmune diseases is the
presence of autoantibodies and inflammation, including
mononuclear phagocytes, autoreactive T lymphocytes and
plasmacells(autoantibodyproducingBcells).Autoimmune
diseases can be classified as organ-specific or nonorgan-
specific depending on whether the autoimmune response is
directed against a particular tissue like the thyroid in
Hashimoto’s thyroiditis, or against widespread antigens
such as cell nuclear antigens in lupus. See also: Auto-
immune Disease; Autoimmune Disease: Animal Models;
Autoimmune Disease: Diagnosis
Antibody-mediated damage
Antibodies or immunoglobulins are a family of glycopro-
teins present in the serum and tissue fluids of all mammals.
Antibodies can be carried on the surface of B cells, acting as
receptors, or free in the blood or lymph. Specific binding of
antigens (self or foreign) causes B cells to produce large
amounts of antigen-specific antibody. These antibodies
provide critical protection against infectious microor-
ganisms immediately following infection and are the key
protective immune response induced by vaccination.
Similarly, self-reactive or autoantibodies are important in
clearing cellular debris induced by inflammation or phys-
ical damage to the body.
A common feature of all autoimmune diseases is the
presence of autoantibodies, which are an important factor
in the diagnosis or classification of the autoimmune
Autoimmune Disease: Mechanisms
3
4. disease. Due to the chronic nature of most autoimmune
diseases, autoantibodies appear long before clinical symp-
toms, providing a good predictive marker for the potential
to develop disease. In fact, the risk of developing an auto-
immune disease rises from about 10% if one autoantibody
is present to around 60–80% if three autoantibodies are
present for a particular autoimmune disease.
Autoantibodies can induce damage to the body by bind-
ing to self-tissues, activating the complement cascade and
inducing lysis and/or removal of cells by phagocytic
immune cells. This occurs in certain forms of haemoly-
tic anaemia when autoantibodies bind to red blood cell
surface antigens inducing lysis of red blood cells. Autoan-
tibodies can also interact with cell-surface receptors, alter-
ing their function. Autoantibodies to the acetylcholine
receptor block transmission at the neuromuscular junction
resulting in myasthenia gravis, while autoantibodies to the
thyrotropin receptor block thyroid cell stimulation result-
ing in Graves’ disease. Self-antigen, autoantibodies and
complement can combine to form injurious immune com-
plexes that deposit in vessels or joints as is observed in
lupus, inflammatory heart disease and arthritis.
Cell-mediated damage
Damage induced by cells of the immune system play a
major pathogenic role in many autoimmune diseases. The
predominant infiltrating cells include phagocytic macro-
phages, neutrophils, self-reactive CD4+ T helper cells and
self-reactive CD8+ cytolytic T cells, with smaller numbers
of natural killer cells, mast cells and dendritic cells.
Immune cells damage tissues directly by killing cells or
indirectly by releasing cytotoxic cytokines, prostaglandins,
reactive nitrogen or oxygen intermediates. Tissue macro-
phages and monocytes can act as antigen-presenting cells
to initiate an autoimmuneresponse, oras effector cells once
an immune response has been initiated. Macrophages act
as killer cells through antibody-dependent cell-mediated
cytotoxicity and by secreting cytokines, such as tumour
necrosis factor (TNF) or interleukin (IL)-1, which act as
protein signals between cells. Macrophages and neutro-
phils damage tissues (and microorganisms) by releasing
highly cytotoxic proteins like nitric oxide and hydrogen
peroxide. Cytokines and other mediators released by
macrophages recruit other inflammatory cells, like neutro-
phils and T cells, to the site of inflammation.
CD4+ T cells have been classified as T helper 1 (TH1) or
T helper 2 (TH2) cells depending on the release of the
cytokines interferon-g (IFN-g) or IL-4, respectively. IFN-g
is a proinflammatory cytokine associated with many
organ-specific autoimmune diseases like type I diabetes
and thyroiditis, while IL-4 activates B cells to produce anti-
bodies and is associated with autoantibody/immune
complex-mediated autoimmune diseases like lupus and
arthritis. Suppressor or regulatory T-cell populations,
including activated CD25+CD4+ regulatory T cells,
exist in peripheral tissues and are important in contro-
lling inflammation and autoimmune responses by killing
autoreactive cells. These regulatory cells also secrete anti-
inflammatory cytokines like IL-10 and transforming
growth factor (TGF)-b that further inhibit TH1 immune
responses, thereby reducing inflammation and autoim-
mune disease. If regulation of self-reactive T-cells and
autoantibody production by regulatory T-cell populations
is disrupted by environmental agents like infections or
toxins, then chronic autoimmune disease may result.
Tolerance
Mechanisms of self-tolerance, defined as a state of nonre-
sponsiveness to self, can be divided into central and periph-
eral tolerance. In central tolerance, immature lymphocytes
in the bone marrow (B cells) and thymus (T cells) that
recognize self-antigens with high affinity die by apoptosis
or programmed cell death. In peripheral tolerance, mature
self-reactive lymphocytes are inactivated, killed or turned
off by regulatory mechanisms including functional anergy,
ignorance and suppression by regulatory T cells. Defects in
tolerance leading to autoimmune disease may occur in one
or multiple tolerance mechanisms. For example, changes
in the apoptotic cell death process, resulting in inappro-
priate cell death or survival or disturbances in clearing
apoptotic cells, are thought to be involved in the patho-
genesis of a number of autoimmune diseases such as
rheumatoid arthritis, lupus and Hashimoto’s thyroiditis.
See also: Autoimmune Disease
Common Mechanisms
Several features are similar between all autoimmune dis-
eases suggesting that common pathogenic mechanisms
lead to the development of autoimmune disease in genet-
ically susceptible individuals. A number of these common
mechanisms have already been discussed in this review.
A feature common to all autoimmune diseases is that they
cluster in families and in individuals. Although genes are
important in determining the likelihood of developing
autoimmunity, in most cases environmental agents are also
necessaryfor autoimmunediseasetodevelop (Figure1). For
example, in animal models of arthritis, disease does not
develop in genetically susceptible animals unless adjuvant
with microbial and self-peptides is administered. Although
some animals (and humans) develop autoimmune diseases
spontaneously due to genetic defects, these models are
not thought to closely represent most cases of human
autoimmune disease. Autoimmune diseases also display a
strong sex-bias, with antibody-dependent systemic auto-
immune diseases occurring more often in females, while
inflammation is often more severe in males. Thus, endog-
enous and exogenous sex hormones are able to alter the
Autoimmune Disease: Mechanisms
4
5. immune response, impacting the progression to autoim-
mune disease. Infectious microorganisms have long been
considered important aetiologic agents in the development
of autoimmune disease. Although their role in patients has
been difficult to substantiate, animal models have demon-
strated that some autoimmune diseases can be induced by
infectious agents such as inflammatory heart disease fol-
lowing coxsackievirus infection. That many diverse micro-
organisms have been associated with a single autoimmune
disease (e.g. viral, bacterial and parasitic infections associ-
ated with inflammatory heart disease) and one type of
microorganism associatedwithmany different autoimmune
diseases (e.g. coxsackievirus infection associated with
diabetes, thyroiditis and inflammation in the heart) further
indicates that infections may induce autoimmune disease by
common pathogenic mechanisms. That is, the inflamma-
tory response to infection is more important than the par-
ticular infectious agent in triggering autoimmune disease.
Innate immunity
Activation of the innate immune system is essential for the
development of a protective adaptive immune response
against infection and for the development of autoimmune
disease. Innate immune cells produce responses to partic-
ular classes of pathogens via pattern recognition receptors
(PRR), such as Toll-like receptors (TLR). Interaction
of pathogen-associated molecular patterns (PAMP) on
microorganisms with PRR on antigen-presenting cells
(APC) like macrophages and dendritic cells results in the
upregulation of surface molecules essential for antigen
presentation and the production of proinflammatory
cytokines. Microbial components of adjuvants, like lipo-
polysaccharide (LPS) or the mycobacteria in complete
Freund’s adjuvant, activate the innate immune response
when administered with self-antigens resulting in autoim-
mune disease in animal models such as collagen-induced
arthritis or cardiac myosin-induced myocarditis. Inocula-
tion of adjuvants without self-antigen does not usually
result in the development of autoimmune disease. Micro-
organisms not only stimulate the immune response by
stimulating PRR like TLR2 and TLR4, but also provide
self-antigens to the immune system by damaging tissues,
both of which are necessary for the development of auto-
immune disease in animal models. Recent studies in animal
models have demonstrated that stimulating the innate
immune response is critical for the later development of
autoimmune disease. Thus, exposure to environmental
agents that alter or influence the innate immune response
may increase the risk of developing an autoimmune disease
in genetically susceptible individuals.
Proinflammatory cytokines
Another pathogenic mechanism common to autoimmune
diseases is the increased production of the cytokines TNF
and IL-1b. These proinflammatory cytokines are produced
during the innate and adaptive immune response and act in
a long-range endocrine manner, affecting immune cells far
removed from the site of infection or inoculation. If TNF
orIL-1blevels areincreased byinoculation ofmice with the
adjuvant LPS (which stimulates TNF and IL-1b produc-
tion) or with either cytokine, autoimmune disease can be
increased in genetically susceptible strains of mice or
tolerance broken in genetically resistant strains. This
indicates that genetic resistance to developing autoim-
mune disease can be overcome by environmental factors
like infections or adjuvants that increase proinflammatory
cytokines. Some epidemiological evidence for this exists in
studies of individuals from regions of the world where the
incidence of autoimmune disease is low (i.e. the Equator)
moving to regions where autoimmune diseases are more
common (i.e. the Northern hemisphere) who go on to
develop autoimmune disease. Since only the environment
changed and not the genetic background of the individual,
environment appears to exert a dominant influence on
whether an individual will develop an autoimmune disease
(Figures 1 and 2). Furthermore, autoimmune disease can be
prevented in humans or animal models if TNF or IL-1
levels are reduced using neutralizing monoclonal antibod-
ies. Recent clinical therapies blocking TNF have produced
remarkable effects in reducing the severity of autoimmune
diseases like rheumatoid arthritis, inflammatory bowel
disease, ankylosing spondylitis, psoriasis and multiple
sclerosis. Experience has shown, however, that it is difficult
to turn off an ongoing autoimmune response and inter-
vention during the earliest stages of antigen recognition is
likely to be necessary for successful treatment or preven-
tion of disease. See also: Autoimmune Diseases: Gene
Therapy; Autoimmune Disease: Treatment
Regulating the immune response
The induction of an immune response must be followed by
downregulation of the response to maintain homeostasis
of the immune system and to prevent or reduce tissue
damage. Likewise, inflammation associated with autoim-
mune disease can be reduced or possibly even prevented if
proinflammatory responses are appropriately downreg-
ulated. Multiple inhibitory pathways keep the immune res-
ponse in check including the inhibitory receptors CTLA-4
and Tim-3, anti-inflammatory cytokines like IL-10 and
TGF-b and specialized cells like regulatory T cells.
Recently, it has been demonstrated that signals leading
to both activation and regulation of the immune response
are initiated during innate immunity. In adjuvant-induced
animal models of autoimmune disease, depletion of reg-
ulatory T cells increases inflammation while administering
these cells can reduce or even prevent disease. Thus, the
balance between effector T cells and regulatory T cells
may determine whether autoimmune disease develops or
Autoimmune Disease: Mechanisms
5
6. persists. Recently, microbial stimulation of TLR was
found to decrease the number of regulatory T cells, which
could be one explanation for the link between infection and
the development of autoimmune disease. Thus, alterations
in mechanisms that regulate inflammation, whether due to
genes or environment, may contribute to the progression
from autoimmunity to autoimmune disease.
Immunotherapy
Patients usually come to medical attention only after
antigenic spread and autoimmune escalation have greatly
expanded the immune response, making it difficult to
intervene at the point of initiation of disease. In the past,
therapies for autoimmune diseases have included immuno-
suppressive or antiviral/antibacterial treatments. Recent
therapies, however, are selectively targeting pathways
common to a number of autoimmune diseases. Therapies
include treatments that target proinflammatory cytokines
like TNF and IL-1b, block costimulatory molecules or use
therapeutic vaccination with regulatory T cells. Recently,
familiar oral medications, such as statins and angiotensin
blockers, widely used to treat other disease conditions such
as allergy and hypertension, have been shown to inhibit
autoimmune inflammation. Since multiple effector mech-
anisms contribute to the immunopathogenesis of autoim-
mune diseases, it is likely that several effector mechanisms
will need to be targeted to effectively treat autoimmune
disease. See also: Autoimmune Diseases: Gene Therapy
Further Reading
Abbas AK, Lohr J, Knoechel B and Nagabhushanam V (2004) T cell
tolerance and autoimmunity. Autoimmunity Reviews 3: 471–475.
Fairweather D and Rose NR (2004) Women and autoimmune diseases.
Emerging Infectious Diseases 10: 2005–2011.
Fairweather D and Rose NR (2005) Inflammatory heart disease: a role
for cytokines. Lupus 14: 646–651.
Feldmann M and Maini RN (2003) Lasker clinical medical research
award. TNF defined as a therapeutic target for rheumatoid arthritis
and other autoimmune diseases. Nature Medicine 9: 1245–1250.
Goodnow CC, Sprent J, Fazekas de St. Groth B and Vinuesa CG (2005)
Cellular and genetic mechanisms of self tolerance and autoimmunity.
Nature 435: 590–597.
Nelson BH (2004) IL-2, regulatory T cells, and tolerance. Journal of
Immunology 172: 3983–3988.
Rose NR and Mackay IR (eds) (2006) The Autoimmune Diseases, 4th
edn. London: Elsevier Academic Press.
Autoimmune Disease: Mechanisms
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