OBC 231 General Pathology

Diseases of the Immune System

Dr. Huda Hammad Dr. Wael Swelam

11/23/2011

Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury

Individuals who mount immune responses against an antigen are said to be

sensitized to that antigen.

When these responses are pathologic or excessive, the manifestations are called

hypersensitivity.

Normally, a system of checks and balances optimizes the eradication of infecting

organisms without serious injury to host tissues.

However, immune responses may be inadequately controlled or inappropriately

targeted to host tissues.

In these situations, the normally beneficial response is the cause of disease.

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury

Causes of Hypersensitivity Diseases
Pathologic immune responses may be directed against different

types of antigens, and may result from various underlying abnormalities: Autoimmunity. 2. Reactions against microbes. 3. Reactions against environmental antigens.
1.

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury

Causes of Hypersensitivity Diseases
1. Autoimmunity:
Normally, the immune system does not react against an individual's

own antigens (self-tolerance).

Sometimes, self-tolerance fails, resulting in reactions against one's

own cells and tissues that are called autoimmunity.

The diseases caused by autoimmunity are referred to as

autoimmune diseases.

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury

Causes of Hypersensitivity Diseases

2. Reactions against microbes:

Many types of reactions against microbial antigens may cause

disease.
In some cases, the reaction may be excessive or the microbial

antigen is unusually persistent.

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury

Causes of Hypersensitivity Diseases

Reactions against microbes

Antibodies produced against microbial immune complexes

T-cell responses against persistent microbes sever inflammatory response

Antibodies / T cells cross-react with a host tissue

During the process of eradicating the infection host tissues injury

Inflammatory Poststreptococcal glomerulonephritis

Granulomas, e.g. Tuberculosis

Rheumatic heart disease

Cytotoxic T cells try to eliminate infected cells, and this normal immune response damages liver cells e.g. Viral hepatitis
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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury

Causes of Hypersensitivity Diseases

Tuberculos granuloma

Viral hepatitis

Poststreptococcal glomerulonephritis
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Rheumatic heart disease

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury

Causes of Hypersensitivity Diseases
3. Reactions against environmental antigens:
Most healthy individuals do not react strongly against common

environmental substances (e.g., pollen, animal dander, or dust mites), but almost 20% of the population is "allergic" to these substances.

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury

Causes of Hypersensitivity Diseases
These hypersensitivity diseases tend to be chronic, often

debilitating, and pose therapeutic challenges.

Since chronic inflammation is a major component of these

disorders, they are sometimes grouped under the term immune-mediated inflammatory diseases.

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury

Types of Hypersensitivity Diseases
Hypersensitivity reactions are traditionally subdivided into four types.

1.
2. 3.

4.

Immediate (type I) hypersensitivity. Antibody-mediated (type II) hypersensitivity. Immune complex-mediated (type III) hypersensitivity. T-cell-mediated (type IV) hypersensitivity.

The first three are variations on antibody-mediated injury, whereas the fourth is

cell mediated.
This classification of immune-mediated disease is not perfect, because several

immune reactions may coexist in one disease.

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Immediate (type I) hypersensitivity

Some of these mediators are released Others, such as cytokines, are within minutes from sensitized mast responsible for the inflammation seen cells causing the intense immediate in late-phase reactions. reactions associated with conditions 11/23/2011 12 such as systemic anaphylaxis.

Sequence of events in immediate (type 1) hypersensitivity

Action Mediator

Vasodilation, increased vascular permeability

Histamine PAF Leukotrienes C4, D4, E4 Neutral proteases that activate complement and kinins Prostaglandin D2
Leukotrienes C4, D4, E4 Histamine Prostaglandins PAF Cytokines (e.g., chemokines, TNF) Leukotriene B4 Eosinophil and neutrophil chemotactic factors (not defined biochemically)
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Smooth muscle spasm

Cellular infiltration

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Immediate (type I) hypersensitivity
Often, the IgE-triggered reaction has two well-defined phases:

(1) the immediate response: vasodilation, vascular leakage, and smooth muscle spasm, within 5 to 30 minutes after exposure to an allergen and subsiding by 60 minutes. (2) a second, late-phase reaction: in 2 to 8 hours later and may last for several days, inflammation and tissue destruction, such as mucosal epithelial cell damage. Dominated by neutrophils, eosinophils, and lymphocytes, especially TH2 cells.
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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Immediate (type I) hypersensitivity
Clinical and Pathologic Manifestations : Systemic anaphylaxis:
Within minutes of an exposure in a

sensitized host, itching, urticaria (hives), and skin erythema appear, followed in short order by profound respiratory difficulty caused by pulmonary bronchoconstriction and accentuated by hypersecretion of mucus.
Laryngeal edema may exacerbate

matters by causing upper airway obstruction.

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Immediate (type I) hypersensitivity
Clinical and Pathologic Manifestations : Systemic anaphylaxis:
The musculature of the entire

gastrointestinal tract may be affected, with resultant vomiting, abdominal cramps, and diarrhea.

Without immediate intervention, there

may be systemic vasodilation with fall in blood pressure (anaphylactic shock), and the patient may progress to circulatory collapse and death within minutes.

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Immediate (type I) hypersensitivity
Clinical and Pathologic Manifestations : Local reactions generally occur when the antigen is confined to a particular site, such as : 1. skin (contact, causing urticaria), 2. gastrointestinal tract (ingestion, causing diarrhea), or 3. lung (inhalation, causing bronchoconstriction).

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Antibody-mediated (type II) hypersensitivity

Caused by antibodies directed against target antigens on

the surface of cells or other tissue components.

The antigens may be normal molecules intrinsic to cell

membranes or extracellular matrix, or they may be adsorbed exogenous antigens (e.g., a drug metabolite).

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Antibody-mediated (type II) hypersensitivity
Antibody-mediated abnormalities are the underlying cause of many human diseases;

examples include:

Autoimmune hemolytic anemia. 2. Autoimmune thrombocytopenic purpura. 3. Pemphigus vulgaris. 4. Vasculitis caused by ANCA. 5. Goodpasture syndrome. 6. Acute rheumatic fever. 7. Myasthenia gravis 8. Graves disease (hyperthyroidism). 9. Insulin-resistant diabetes. 10. Pernicious anemia.
1.
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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Antibody-mediated (type II) hypersensitivity Mechanisms of Antibody-Mediated Diseases: A.

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Antibody-mediated (type II) hypersensitivity Mechanisms of Antibody-Mediated Diseases: C. Antibodies can bind to cell surface receptors or essential molecules, and cause functional derangements (either inhibition or unregulated activation) without cell injury, e.g. myasthenia gravis, Graves disease (hyperthyroidism).

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Immune complex-mediated (type III)

Caused by antibodies binding to antigens to form complexes

that circulate and may deposit in vascular beds and stimulate inflammation, typically secondary to complement activation. Tissue injury in these diseases is the result of the inflammation. The antigens in these complexes may be exogenous antigens, such as microbial proteins, or endogenous antigens, such as nucleoproteins. It is only when these complexes are produced in large amounts, persist, and are deposited in tissues that they are pathogenic.
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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases

1) Formation of antigen-antibody complexes in the circulation.

Immune complex-mediated (type III)

Systemic

2) Deposition of the immune complexes in various tissues, thus initiating 3) An inflammatory reaction in various sites throughout the body Excess amount of initial antibody immune complexes precipitated at the site of injection and trigger the same inflammatory reaction as in systemic immune complex disease

Local

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Immune complex-mediated (type III)
Disease
Systemic lupus erythematosus Poststreptococcal glomerulonephritis

Antigen Involved
Nuclear antigens Streptococcal cell wall antigen(s); may be "planted" in glomerular basement membrane

Clinicopathologic Manifestations
Nephritis, skin lesions, arthritis, others Nephritis

Polyarteritis nodosa
Reactive arthritis Serum sickness

Hepatitis B virus antigen

Bacterial antigens (Yersinia)

Hepatitis B virus antigen

Acute arthritis

Various proteins, such as Arthritis, vasculitis, nephritis foreign serum protein (horse anti-thymocyte globulin) Various foreign proteins Cutaneous vasculitis
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Arthus reaction (experimental)

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases T-cell-mediated (type IV) hypersensitivity Mechanisms of T-cell-mediated (type IV) hypersensitivity reactions:

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases T-cell-mediated (type IV) hypersensitivity

Mechanisms of T-cell-mediated (type IV) hypersensitivity reactions: B. Direct cell cytotoxicity, mediated by CD8+ T cells.

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Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases T-cell-mediated (type IV) hypersensitivity

This group of diseases has received great interest because many

of the newly designed biologic therapies developed to target abnormal T-cell reactions.
Several autoimmune disorders, as well as pathologic reactions to

environmental chemicals and persistent microbes, are now known to be caused by T cells.

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Disease

Specificity of Pathogenic T cells

Clinicopathologic Manifestations

Type 1 diabetes mellitus

Antigens of pancreatic islet cells (insulin, glutamic acid decarboxylase, others)

Protein antigens in CNS myelin (myelin basic protein, proteolipid protein) Unknown antigen in joint synovium (type II collagen?); role of antibodies? Protein antigens of peripheral nerve myelin Unknown antigen; may be derived from intestinal microbes

Antigens of pancreatic islet cells (insulin, glutamic acid decarboxylase, others)

Demyelination in CNS with perivascular inflammation; paralysis, ocular lesions Demyelination in CNS with perivascular inflammation; paralysis, ocular lesions Demyelination in CNS with perivascular inflammation; paralysis, ocular lesions Chronic inflammation of ileum and colon, often with granulomas; fibrosis, stricture Dermatitis, with itching; usually 11/23/2011 short-lived, may be chronic with persistent exposure

Multiple sclerosis

Rheumatoid arthritis

Peripheral neuropathy; GuillainBarr syndrome? Inflammatory bowel disease (Crohn's disease)

Contact dermatitis
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Environmental chemicals, e.g., poison ivy (pentadecylcatechol)

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Rejection of transplants
Transplantation problems
Surgical difficulties

Graft rejection
Organ shortage

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Transplant Immunology Outline: Graft compatibility

Rejection = Autograft Recipient recognizes graft as foreign, and destroys it Within same person

Isograft
Allograft Xenograft

Between identical twins

Between genetically different people Between different species

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Histocompatibility
Histocompatible: antigenically similar to the host Histoincompatible: antigenically different from the host

MHC antigens are the most important

ABO antigens are also important Minor histocompatiblity antigens are less important

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Compatibility: HLA complex

Gene collection on chromosome 6 Three regions: class I, class II, class III Class I gene products HLA-A, HLA-B, HLA-C expressed on nearly all cells present antigen to TC cells

Class II gene products DP, DQ, DR expressed on antigen-presenting cells present antigen to TH cells
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Compatibility

MHC class

II

III

Region
Gene products

A
HLAA

B
HLAB

C
HLAC

DP

DQ

DR

C4, C2, BF
TNF- proteins TNF- C'

DP

DQ

DR

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Compatibility

parents
a/b c/d

four possible haplotype combinations of children a/c a/d b/c b/d

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Compatibility
HLA alleles A a b haplotypes 1 2 B 7 8 C w3 w2 DR 2 3 DQ DP 1 2 1 2

c
d

3
11

44
35

w4
w1

4
7

1
3

3
4

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Compatibility
ice cream
pop fruit cookie veggie

yum yum

haplotypes

De w

Vault

d
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Compatibility: HLA inheritance

The more matching alleles between donor and host, the better! Matching the class II antigens is more important than matching the
class I antigens.

One or two class I mismatches = no big deal

One or two class II mismatches = big deal Mismatches in both class I and II = very big deal

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number of mismatches
100

Class I

Class II

0 1 or 2 3 or 4
graft survival, %

0 0 0 1 or 2 1 or 2 1 or 2

50

0 1 or 2 3 or 4

12

time after transplant, months

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Transplant Immunology Outline

Introduction Graft compatibility Graft rejection

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Rejection
Any two people (except identical twins) will express some
HLA proteins that are different.

Every recipient will recognize, and react against, at least

some foreign antigens in the graft

Rejection is complex, with lots of killing mechanisms.

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Rejection
How do recipient cells know which cells to kill?

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Rejection
Two mechanisms of rejection

T-cell-mediated rejection Antibody-mediated rejection

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T-cell mediated rejection

CD8+ CTLs kill graft cells directly CD4+ cells trigger a delayed hypersensitivity reaction

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CTL Killing

Delayed Hypersensitivity

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Antibody-mediated rejection
Preformed antibodies Anti-HLA or anti-ABO Rejection occurs immediately
(hyperacute) Antibodies cause thrombosis Rare these days

Newly-made antibodies Appear within days to years Usually directed against graft
endothelium

Cause damage by:

Helping complement kill graft cells Opsonizing graft cells (yummy!)

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Antibody-dependant cell-mediated cytotoxicity (ADCC)

Target cell is coated with IgG
Effector cell* has receptors for Fc fragment Effector cell binds to target cell Target cell is lysed

50*

Macrophage, Neutrophil, or NK Cell

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Clinical types of Rejection

Hyper-acute rejection Within hours Preexisting anti-donor antibodies Rare these days Accelerated is similar Chronic rejection Months to years after transplant Humoral and cell-mediated mechanisms Hard to prevent Hard to treat

Acute rejection Starts at about 10 days Cellmediated

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Acute cellular (t)

Acute humoral

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Chronic

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Autoimmune Diseases
The immune reaction to self-antigens, or autoimmunity, is

the cause of certain human diseases.

A growing number of entities have been attributed to

this process (see table in next slide).

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Organ-Specific Hashimoto thyroiditis Autoimmune hemolytic anemia Autoimmune atrophic gastritis of pernicious anemia Multiple sclerosis Autoimmune orchitis Goodpasture syndrome Autoimmune thrombocytopenia Insulin-dependent diabetes mellitus Myasthenia gravis Graves' disease Primary biliary cirrhosis*

Systemic Systemic lupus erythematosus Rheumatoid arthritis Sjgren syndrome Reiter syndrome Inflammatory myopathies* Systemic sclerosis (scleroderma)* Polyarteritis nodosa*

Autoimmune (chronic active) hepatitis* Ulcerative colitis

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*The evidence supporting an autoimmune basis of these disorders is not strong.

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Autoimmune Diseases
The evidence that the diseases listed in the previous table are the

result of autoimmune reactions is more persuasive for some than for others.
For example, the presence of multiple autoantibodies accounts for

many of the clinical and pathologic manifestations of SLE.

Moreover, these autoantibodies can be identified within lesions by

immunofluorescence and electron-microscopic techniques.

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Autoimmune Diseases
In many other disorders, an autoimmune etiology is

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suspected but is unproven. In some cases of apparent autoimmunity, the response may be directed against an exogenous antigen, such as a microbial protein. Autoimmune diseases range from those in which specific immune responses are directed against one particular organ or cell type, to multisystem diseases. In the systemic diseases, the lesions affect principally the connective tissue and blood vessels of the various organs involved. These diseases are often referred to as "collagen vascular" or "connective tissue" disorders. 11/23/2011

Autoimmune Diseases: Self-Tolerance

Autoimmunity implies loss of self-tolerance.
Immunological tolerance is unresponsiveness to an antigen

that is induced by exposure of specific lymphocytes to that antigen.

Self-tolerance refers to a lack of immune responsiveness to

one's own tissue antigens.

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Autoimmune Diseases
Self-Tolerance
During the generation of billions of antigen receptors in

developing T and B lymphocytes, receptors are produced that can recognize self-antigens.
Several mechanisms work in concert to prevent immune

reactions against one's own antigens.

These mechanisms are broadly divided into two groups:

central tolerance and peripheral tolerance.

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Autoimmune Diseases
Self-Tolerance Central tolerance
Immature lymphocytes that recognize self-antigens in the central (generative) lymphoid organs are killed by apoptosis.
In the B-cell lineage, some of the self-reactive lymphocytes switch to new antigen receptors that are not self-reactive
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Peripheral tolerance
Mature lymphocytes that recognize self-antigens in peripheral tissues undergo one of the following:
They become functionally inactive (anergic), Or are suppressed by regulatory T lymphocytes, Or die by apoptosis.

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Autoimmune Diseases
Self-Tolerance
The variables that lead to a failure of self-tolerance and the

development of autoimmunity include: 1. Inheritance of susceptibility genes that may disrupt different tolerance pathways. 2. Infections and tissue alterations that may expose selfantigens and activate APCs and lymphocytes in the tissues, altering the recognition of self-antigens.

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Pathogenesis of autoimmunity
Autoimmunity arises from many causes, including: 1) Inheritance of susceptibility genes that may interfere with selftolerance, 2) Environmental triggers (inflammation, other inflammatory stimuli) that promote lymphocyte entry into tissues, 3) Activation of self-reactive lymphocytes, and tissue injury.
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Autoimmune Diseases
Systemic Lupus Erythematosus
The fundamental defect in SLE is a failure to maintain

self-tolerance. A large number of autoantibodies is produced, classically including antinuclear antibodies (ANAs),that can damage tissues either directly or in the form of immune complex deposits.

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Lupus erythematosis pathogenesis

Genetic factors

B cell reactivity

alter the function of T cells, antigen-presenting cells & cytokines production

B cells to enhance the function of other cells

autoantibody production

Organ damage
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Autoimmune Diseases
Systemic Lupus Erythematosus
1997 Revised Criteria for Classification of Systemic Lupus Erythematosus

Malar rash Oral ulceration

Malar rash

Photosensitivity

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rash

Arthritis 11/23/2011

Autoimmune Diseases
Systemic Lupus Erythematosus
1997 Revised Criteria for Classification of Systemic Lupus Erythematosus

Serositis

Neurologic disorder

Renal disorders
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Autoimmune Diseases
Systemic Lupus Erythematosus
1997 Revised Criteria for Classification of Systemic Lupus Erythematosus

Hematologic disorder

Immunologic disorder

Hemolytic anemia: with reticulocytosis, Leukopenia: <4.0 109 cells per liter (4000 cells per mm3) total on two or more occasions Lymphopenia: <1.5 109 cells per liter (1500 cells per mm3) on two or more occasions Thrombocytopenia: <100 109 cells per liter (100 103 cells per mm3) in the absence of offending drugs
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Anti-DNA antibody to native DNA in abnormal titer Anti-Sm: presence of antibody to Sm nuclear antigen Positive finding of antiphospholipid antibodies

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Autoimmune Diseases
Systemic Lupus Erythematosus
1997 Revised Criteria for Classification of Systemic Lupus Erythematosus

11. Antinuclear antibody: An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome.

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Immune Deficiencies: Basic Concepts

Immune deficiencies
primary (inherited) secondary (to infection, immunosuppression, etc.)

Patients more susceptible to infections and cancer Type of infection varies:

Ig, C or phagocytic cell defect: bacterial infection T cell defect: viral and fungal infections

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Primary Immune Deficiency Diseases: Basic Concepts

Rare! Genetic

Can affect any part of immune system:

Adaptive (humoral or cellular) Innate (C, phagocytes, NK cells)

Typical patient: infant with recurrent infections

Primary importance for our class: boards

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SCID

SCID

DiGeorge syndrome X-linked agammaglobulinemia

SCID

Hyper-IgM syndrome

IgA deficiency

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Primary immune deficiencies

X-Linked Agammaglobulinemia Common Variable Immunodeficiency (CVID) Hyper-IgM Syndrome Selective IgA Deficiency

Combined T-cell and B-cell (antibody)

deficiencies

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X-linked Agammaglobulinemia

Pre-B cells cant differentiate into B cells

Patients have no immunoglobulin

Affects males Presents at 6 months of age (maternal Ig gone)

Recurrent bacterial infections

Treatment: intravenous pooled human Ig

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Common variable immunodeficiency

Group of disorders characterized by
defective antibody production

Basis of Ig deficiency is variable (hence the

name) and often unknown

Affects males and females equally

Presents in teens or twenties

Patients more susceptible to infections, but

also to autoimmune disorders and lymphoma!

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Severe Combined Immunodeficiency

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Examples of Infections in Immunodeficiencies

Pathogen Type Bacteria

T-Cell-Defect
Bacterial sepsis

B-Cell Defect
Streptococci, staphylococci, Haemophilus

Granulocyte Defect Staphylococci, Pseudomonas

Complement Defect

Neisserial
infections, other pyogenic bacterial infections

Viruses

Cytomegalovirus, Epstein-Barr Enteroviral virus, severe varicella, chronic encephalitis infections with respiratory and intestinal viruses

Fungi and parasites

Candida, Pneumocystis carinii Severe intestinal giardiasis

Candida, Nocardia, Aspergillus

Special features

Aggressive disease with Recurrent opportunistic pathogens, failure sinopulmonary to clear infections infections, sepsis, chronic meningitis 11/23/2011

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A good way to study immune deficiencies

Disease XLA Transmission
X-linked

Defect
No mature B cells; no Ig

Clinical stuff
Infant with recurrent bacterial infections

CVID
IgA deficiency Hyper-IgM DiGeorge SCID

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AIDS(SECONDARY IDS)
Etiology: HIV Pathogenesis: Infection, Latency, Progressive T-Cell loss Morphology: MANY Clinical Expressions: Infections, Neoplasms, Progressive Immune Failure, Death, HIV+, HIV-RNA (Viral Load)
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Epidemiology
Homosexual: (40%, and declining)
Intravenous drug usage

(25%) Heterosexual sex (10% and rising)

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Reverse transcriptase
The enzyme reverse transcriptase (RT) is used by retroviruses to transcribe
their single-stranded RNA genome into single-stranded DNA and to subsequently construct a complementary strand of DNA, providing a DNA

double helix capable of integration into host cell chromosomes.

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Pathogenesis

Attaching
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Budding
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Pathogenesis
Early budding Late budding

Mature new virions

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General immune abnormalities

Lymphopenia Decreased t-cell function B-cell activation, polyclonal Altered monocyte/macrophage function

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AIDS related Infections

Protozoal/Helminthic:
Cryptosporidium, PCP (Pneumocystis Carinii Pneumonia), Toxoplasmosis

Fungal:
Candida, and the usual 3

Bacterial:
TB, Nocardia, Salmonella
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Viral: CMV, HSV, VZ (Herpes Family)

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PCP

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CRYPTOSPORIDIUM

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Caseating granuloma

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Cancers related to AIDS

Kaposi sarcoma
B-cell lymphomas CNS lymphomas

Cervix cancer, squamous cell

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