DISEASES OF THE

IMMUNE SYSTEM

Ria L. Bilog, MD, DPSP

 Normal Immune Response
 Immunity
 protection from infectious pathogens

 Innate immunity (natural or native)

 mechanisms that are ready to react to infections even before
they occur, and that have evolved to specifically recognize
and combat microbes
 Adaptive immunity (acquired or specific)
 mechanisms that are stimulated by (“adapt to”) microbes
and are capable of recognizing microbial and nonmicrobial
substances
Innate Immunity
 recognition of microbes and damaged cells
 activation of various mechanisms
 elimination of the unwanted substances
 Components of Innate Immunity

 Epithelia- mechanical barriers; produce antimicrobial

molecules
 Monocytes and neutrophils- phagocytes in the blood
 Dendritic cells- antigen presenting function; sense microbes
and cell damage and stimulate the secretion of cytokines
 Natural killer cells- provide early protection against many
viruses and intracellular bacteria
 Mast cells- produce mediators of inflammation
 Innate lymphoid cells
 Soluble proteins
 Adaptive Immunity

 Humoral immunity- protects against extracellular microbes

and their toxins; mediated by B lymphocytes and their
secreted products (antibodies/ immunoglobulins)
 Cell-mediated (or cellular) immunity- for defense against
intracellular microbes; mediated by T lymphocytes
 Cells Of The Immune System

Naive* lymphocytes
recognize antigens
Activation

Effector cells Memory cells*

- eliminate microbes
 Cells Of The Immune System
1. T lymphocytes – constitute 60-70% of lymphocytes in the blood
- cytotoxic, helper and regulatory T cells
- in paracortex of lymph nodes, periarteriolar lymphoid sheaths of
spleen
- markers: CD3, CD4 (helper T-cell, 60%)
or CD8 (cytotoxic/killer T-cell, 30%)
T lymphocytes and TCR
❑ recognize a cell-bound
antigen by means of an
antigen-specific T-cell receptor
(TCR)
❑ CD4 and CD8 –

co-receptors in T-cell
activation
❑ αβ TCR – recognize antigens
displayed by MHC molecules
on the surfaces of antigen-
presenting cells
✓ CD4 = Class II MHC
✓ CD8 = Class I MHC
2. B lymphocytes – constitute 10-20% of
circulating lymphocytes
- in peripheral lymphoid tissues
(follicles of the cortex of lymph nodes
and spleen, and mucosa-associated
lymphoid tissues)
- recognize antigen via the B-cell
antigen receptor complex
(Membrane-bound IgM and IgD)
- develop into plasma cells that
secrete antibodies
 Cells Of The Immune System

3. Dendritic cells (Interdigitating dendritic cells)

- present antigens to T cells when recruited in T-cell zones of
lymphoid organs
- e.g. Langerhans cells*
Follicular dendritic cells – present in the germinal centers of
lymphoid follicles in the spleen and lymph nodes
- present antigens to B cells
 Cells Of The Immune System
4. Macrophages – APC
- phagocytosis
- key effector cells in certain forms of cell-
mediated immunity
- participate in the effector phase of
humoral immunity
5. Natural Killer Cells - destroy abnormal cells without
prior exposure
- “large granular lymphocytes”
 Tissues Of The Immune System
1. Generative Lymphoid organs- primary, or central
lymphoid organs (thymus & bone marrow)
– where T and B lymphocytes develop or mature*
2. Peripheral lymphoid organs – secondary lymphoid
organs where adaptive immune response are initiated
- concentrate antigens, APCs, and lymphocytes

A. Lymph nodes – concentrate antigens from lymph

B. Spleen – trap blood-borne antigens
C. Cutaneous and mucosal lymphoid systems (GI and respiratory
tracts, pharyngeal tonsils, Peyer’s patches)
 Hypersensitivity
 Immune deficiency
 Autoimmune
 Amyloidosis
 Hypersensitivity: Immunologically
Mediated Tissue Injury

 Elicited by exogenous environmental antigens or

endogenous self antigens
 Imbalance between the effector mechanisms and the
control mechanisms
 Associated with the inheritance of particular susceptibility
genes
 Mechanisms of tissue injury are the same as the effector
mechanisms of defense
Classification of Hypersensitivity Diseases

 Immediate Hypersensitivity (Type I Hypersensitivity)

 Antibody-mediated Disorders (Type II Hypersensitivity)
 Immune Complex–mediated Disorders (Type III
Hypersensitivity)
 Cell-mediated Immune Disorders (Type IV
Hypersensitivity)
Immediate (Type I) Hypersensitivity
 Allergy
 Rapid immunologic reaction occurring in a previously
sensitized individual
 Triggered by the binding of an antigen to IgE
antibody on the surface of mast cells
 Systemic disorder or local reaction
 Immediate reaction- characterized by vasodilation,
vascular leakage, and smooth muscle spasm or
glandular secretions
 Late-phase reaction- characterized by infiltration of
tissues with eosinophils, neutrophils, basophils,
monocytes, and CD4+ T cells, as well as tissue
destruction

 Most immediate hypersensitivity disorders are caused

by excessive TH2 responses which stimulate IgE
production and promote inflammation
Mediators of Immediate Hypersensitivity
 Preformed Mediators- first to be released
 Vasoactive amines (Histamine)
 Enzymes

 Proteoglycans

 Lipid Mediators
 Leukotriene B4, C4, D4
 Prostaglandin D2

 Platelet-activating factor

 Cytokines
 TNF, IL-1, chemokines, IL-4
Antibody-Mediated (Type II)
Hypersensitivity

 Opsonization and Phagocytosis

 Inflammation
 Cellular Dysfunction
Immune Complex–Mediated (Type III)
Hypersensitivity
 antigen combines with antibody in the
circulation
 complexes may be formed at sites where

antigen has been “planted” previously

T Cell–Mediated (Type IV)
Hypersensitivity
 caused by inflammation resulting from
cytokines produced by CD4+ T cells and cell
killing by CD8+ T cells
Immunodeficiency Syndromes

 Primary immunodeficiency disorders

› Affect the humoral and/or cellular arms of adaptive immunity
or the defense mechanisms of innate immunity
› Most are detected in infancy between 6 months and 2 years
of life
 Secondary immunodeficiency states
› May arise as complications of cancers, infections, malnutrition,
or side-effects of immunosuppression, irradiation, or
chemotherapy for cancer and other diseases
Acquired Immunodeficiency Syndrome
(AIDS)
 Human immunodeficiency virus (HIV)
 HIV-1 and HIV-2
 Immune system and the CNS
 Hallmark: Profound immune deficiency, primarily
affecting cell- mediated immunity
 Structure Of HIV
1. Virus core
a) major capsid protein p24 - the most readily
detected viral antigen and is the target for the
antibodies that are used for the diagnosis of
HIV infection
b) nucleocapsid protein p7/p9
c) 2 copies of genomic RNA (with gag, pol and
env genes)
d) 3 viral enzymes – protease, reverse
transcriptase, and integrase
2. p17 – matrix protein that surrounds viral core
3. Virion envelope
4. Viral glycoproteins gp120 and gp41 - critical for
HIV infection of cells.
Epidemiology
 Homosexual or bisexual men
 Intravenous drug abusers

 Hemophiliacs

 Recipients of blood and blood components

 Heterosexual contacts of members of other

high-risk groups
 HIV infection of the newborn
Routes Of Transmission
 Sexual transmission
 Enhanced by coexisting sexually transmitted diseases
 2 ways of transmission:

1. Direct inoculation into the blood vessels breached by

trauma
2. Infection of dendritic cells or CD4+ cells within the
mucosa
 Parenteral transmission
 Mother-to-infant transmission
 Life Cycle of HIV

Co-
receptors:
CCR5 and
CXCR4
Mechanisms Of Immune Deficiency
 Loss of CD4+ T cells
 Defective macrophage and dendritic cell

functions
 Destruction of architecture of lymphoid tissues
 Natural History of HIV Infection

1. Acute retroviral syndrome - self-limited acute illness with

nonspecific symptoms, including sore throat, myalgias, fever,
weight loss, and fatigue, resembling a flulike syndrome
2. Chronic infection: Phase of clinical latency - few or no clinical
manifestations of the HIV infection are present.
- Patients are either asymptomatic or develop minor opportunistic
infections, such as oral candidiasis (thrush), vaginal candidiasis,
and perhaps mycobacterial tuberculosis
 Natural History of HIV Infection

3. AIDS - characterized by a breakdown of host defense, and

severe, life-threatening clinical disease
- serious opportunistic infections, secondary neoplasms, or
clinical neurologic disease emerge
Clinical Features
 Fever
 Weight loss

 Diarrhea

 Generalized lymphadenopathy

 Multiple opportunistic infections

 Neurologic disease

 Secondary neoplasms

Treatment: HAART
Let’s stop
Please let’shere
stopfor a
here
while….
for now….
(5 minute-break)
Immunologic Tolerance
 Unresponsiveness to an antigen induced by
exposure of lymphocytes to that antigen

 Self-tolerance- lack of responsiveness to an individual’s

own antigens
Central Tolerance
 Immature self-reactive T and B lymphocyte
clones that recognize self antigens during their
maturation in the central lymphoid organs are
killed or rendered harmless
 Negative selection or deletion- T cells
 Receptor editing- B cells
Peripheral Tolerance
 Anergy
 Suppression by regulatory T cells

 Deletion by apoptosis
Mechanisms of Autoimmunity: General
Principles
 Defective tolerance
or regulation
 Abnormal display

of self antigens
 Inflammation or an
initial innate
immune response
General Features of Autoimmune
Diseases
 Chronic, with relapses and remissions, and the
damage is often progressive
 epitope spreading
 Clinical and pathologic manifestations are
determined by the nature of the underlying
immune response
 Systemic Lupus Erythematosus (SLE)
 Injury is caused by deposition of immune complexes
and binding of antibodies to various cells and
tissues
 Autoantibodies (ANAs)

 Injury to the skin, joints, kidney, and serosal

membranes is prominent
 Predominantly affects women of childbearing age
Etiology and Pathogenesis of SLE
 The fundamental defect is a failure of the
mechanisms that maintain self-tolerance
 Genetic Factors

 Immunologic Factors

 Environmental Factors- ultraviolet (UV) light,

gender bias, drugs

 SLE Clinical Features

➢ Young woman with butterfly rash over the face

➢ Fever, photosensitivity
➢ Characterized by flare-ups and remissions for
years or decades
➢ Treatment: Steroids, immunosuppressive drugs
➢ Cause of death: Renal failure and infections
Sjögren Syndrome
 Chronic disease characterized by dry eyes
(keratoconjunctivitis sicca) and dry mouth
(xerostomia) resulting from immunologically
mediated destruction of the lacrimal and
salivary glands
 ANAs are detected in 50% to 80% of patients

 SS-A (Ro) and SS-B (La) can be detected in

90% of patients
 Diagnosis - Biopsy of the lip (to examine minor
salivary glands)
Systemic Sclerosis (Scleroderma)
 Chronic inflammation thought to be the result of
autoimmunity
 Widespread damage to small blood vessels

 Progressive interstitial and perivascular fibrosis

in the skin and multiple organs

 Characterized by excessive fibrosis throughout

the body
 Diffuse scleroderma- widespread skin
involvement at onset, with rapid progression
and early visceral involvement
 Limited scleroderma- skin involvement is often

confined to fingers, forearms, and face

 CRESTsyndrome- Calcinosis, Raynaud phenomenon,
Esophageal dysmotility, Sclerodactyly, and
Telangiectasia
 Raynaud phenomenon
 Dysphagia
 Respiratory difficulties
 Malignant
hypertension
 Renal failure
 Alimentary tract- progressive atrophy and
collagenous fibrous replacement of the
muscularis
 Musculoskeletal system- inflammation of the

synovium, with hypertrophy and hyperplasia of

the synovial soft tissues; fibrosis later ensues
 Kidneys- vascular lesions
 Lungs- pulmonary hypertension and interstitial

fibrosis
 Heart- pericarditis with effusion, myocardial
fibrosis, and thickening of intramyocardial
arterioles
Amyloidosis
 extracellular deposits of fibrillar proteins are
responsible for tissue damage and functional
compromise
 a pathologic proteinaceous substance, deposited
in the extracellular space in various tissues and
organs of the body
 appears as an amorphous, eosinophilic, hyaline,
extracellular substance that, with progressive
accumulation, encroaches on and produces
pressure atrophy of adjacent cells
 Amyloidosis

Physical Nature of Amyloid -

made up largely of
continuous, nonbranching
fibrils
 Amyloidosis
3 most common forms of amyloid:
1. AL (amyloid light chain) – derived from Ig light chains produced in
plasma cells
- multiple myeloma
2. AA (amyloid-associated) – non-Ig protein synthesized by the liver
- associated with chronic inflammation,
and is often called secondary amyloidosis
3. β amyloid (Aβ) – core of cerebral plaques found in Alzheimer
disease

Other biochemical distinct proteins found in amyloid deposits:

 Transthyretin/TTR (Senile systemic amyloidosis)

 β2-microglobulin (Hemodialysis-Associated Amyloidosis)