Pathphys Ch 4

Central lymphoid organs

Bone marrow and thymus

1. Composed of reticular tissue

2. Reticular tissue provides a framework for the organs and allows immune cells to circulate and encounter antigens.

Peripheral lymphoid organs

Lymph nodes, spleen, tonsils, appendix, Peyer patches, and mucosa-associated lymphoid tissue in the respiratory, gastrointestinal, and reproductive systems

1. Recognize and process antigens

2. Promote cellular interactions necessary for adaptive immune responses

Immune

The central and peripheral lymphoid organs contain large quantities of ____ cells

lymph channels, blood vessels, and capillaries

All lymphoid organs are connected by networks of ___, ____, ____.

1. These networks allow immune cells to circulate throughout the body so they can seek out and destroy foreign material.

2. Examples of foreign material: Infectious agents, toxins, pollen, dust, transplanted tissue

Immune response

Process by which the body recognizes and defends against foreign material

1. Triggered when receptors in the body bind with antigens on the surface of foreign materials

2. May be either primary or secondary

Primary immune response

Occurs upon initial exposure to an antigen

Secondary immune response

Occurs upon subsequent exposure to an antigen

• Rise in antibodies occurs more rapidly because memory cells recognize the antigen and can mount a faster immune response.

Protect ; Prevent ; Mediate

Immune system has three primary functions:

1. __ against invading microorganisms

2. ____ cancer cell proliferation

3. ___ healing of damaged tissue

If the immune system cannot perform these functions properly, a variety of illnesses may result—including hypersensitivity reactions and autoimmune disorders.

Hypersensitivity disorders

Result from inappropriate activation of the immune system

Type I reactions

IgE-mediated disorders

Also called allergic reactions, often occur within minutes of exposure to an antigen

Many ____ reactions have two phases.

Hypersensitivity

Type II reactions

Antibody-mediated disorders

1. Mediated by IgG or IgM antibodies directed against target antigens on cell surfaces or in connective tissues

2. Target antigens may be endogenous (present on membranes of body cells) or exogenous (absorbed on the membrane surface).

3. Three types of antibody-mediated mechanisms are involved in ___

1. Complement- and antibody receptor–mediated phagocytosis

2. Complement- and antibody receptor–mediated inflammation

3. Antibody-mediated cellular dysfunction

• Examples: Transfusion of a type B blood to a person type A

Hypersensitivity

Type III reactions

Complement-mediated immune disorders

Mediated by formation of insoluble antigen–antibody complexes, complement fixation, and localized inflammation

1. Immune complexes formed in circulation produce damage when in contact with the vessel lining or deposited in tissues.

2. Once deposited, the immune complexes elicit an inflammatory response by activating complement.

3. Complement activation leads to recruitment of neutrophils and other inflammatory cells, which are responsible for injury.

Hypersensitivity

Type IV reactions

T-cell-mediated disorders

• Principal mechanism of response to many microorganisms and extracellular agents such as fungi, protozoa, and parasites

• Can cause cell death and tissue injury in response to chemical antigens or self-antigens

• Mediated by specifically sensitized T lymphocytes

1. Can be the cause of several diseases, including allergic contact dermatitis

• Diagnosis of contact dermatitis is made by observing the distribution of lesions on the skin surface.

• Patch testing may be used to determine specific allergens.

• Treatment is often limited to removal of the irritant and topical preparations, although severe reactions may require systemic corticosteroid therapy.

Hypersensitivity

Allergens

Antigens that provoke a type I reaction

• Common ones include pollen, dust mites, animal dander, foods, and chemicals like penicillin

• Exposure may occur via inhalation, ingestion, injection, or skin contact

• Portal of entry often determines whether a person’s reaction is local or systemic

T-helper cells, Mast cells, Basophils

Three types of cells are central to type I hypersensitivity reactions ___, __, ___

Type 1 T-helper (Th1)

Cells stimulate differentiation of B cells into IgM- and IgG-producing plasma cells

Type 2 T-helper (Th2)

Cells stimulate differentiation of B cells into IgE-producing plasma cells.

Mast cells

Granules within these cells release mediators that initiate early events in type I reactions.

Distributed throughout connective tissue, with large numbers found beneath the skin, in the mucous membranes, and adjacent to blood and lymph vessels

Basophils

Type of blood cell

Like mast cells, they contain granules that release mediators involved in the early stages of a type I reaction.

IgE

All type I reactions follow the same sequence of events.

1. First, allergen-specific ___ antibodies attach to receptors on the surface of mast cells or basophils, sensitizing the cells.

2. With subsequent exposure, the sensitizing allergen binds to the cell-associated ___

3. Binding triggers degranulation of the sensitized mast cells or basophils and release of their preformed mediators

Primary or initial-phase response

1. Occurs within 5 to 30 minutes of antigen exposure and subsides within 60 minutes of exposure

2. Mediated by mast cell degranulation and the release of chemicals that cause kinin generation, vasodilation, vascular leakage, and smooth muscle contraction

Anaphylactic Reactions

1. Anaphylaxis

2. Results from presence of antigen introduced via injection, insect sting, or absorption through skin or gastrointestinal mucosa

3. Clinical manifestations (in order of appearance):

• Itching, urticaria, and skin erythema

• Bronchospasm and respiratory distress

• Vomiting, abdominal cramps, and diarrhea

• Laryngeal edema and obstruction

• Widespread edema

• Vascular shock due to vasodilation

Anaphylaxis

A systemic life-threatening type I hypersensitivity reaction

Medical emergency that requires immediate intervention to prevent shock and death

Atopic Reactions

Also called local reactions often occur when an antigen is confined to a particular site of exposure.

1. Common atopic disorders:

1. Urticaria

2. Allergic rhinitis

3. Atopic dermatitis

4. Food allergies

5. Some forms of asthma

Atopic

Term referring to a genetically determined hypersensitivity to common environmental allergens mediated by an IgE–mast cell reaction

Allergic Rhinitis

1. Symptoms include sneezing, itching, and rhinoconjunctivitis (watery discharge from nose and eyes).

2. Frequently associated with other chronic airway disorders, such as sinusitis and bronchial asthma

3. Severe attacks may be accompanied by systemic malaise, fatigue, and muscle soreness from sneezing.

Food Allergy

May be caused by any food, but some are especially common triggers:

1. Milk

2. Eggs

3. Peanuts

4. Soy

5. Tree nuts

6. Fish

7. Shellfish

1. In some cases, the allergenicity may be changed by heating or cooking.

2. Primary target may be the skin, gastrointestinal tract, or respiratory system.

3. Reactions can be acute or chronic

• Acute reactions: Hives, anaphylaxis

• Chronic reactions: Asthma, atopic dermatitis, gastrointestinal disorders

Phagocytosis, inflammation, dysfunction

Three types of antibody-mediated mechanisms are involved in type II reactions

1. Complement- and antibody receptor–mediated ___

2. Complement- and antibody receptor–mediated ___

3. Antibody-mediated cellular ___

Autoimmune Disease

1. Caused by a breakdown in the immune system’s ability to differentiate between self- and nonself-antigens

2. Can affect any cell or tissue in the body

3. May be tissue-specific or affect multiple organs and systems

4. Diseases are Complex, it is unlikely that any single factor is to blame for their development.

Self-tolerance

The ability of the immune system to differentiate foreign antigens from self-antigens

1. Necessary for proper function of the immune system

2. Requires the presence of several chemical messengers and costimulatory signals

3. Results from both central and peripheral mechanisms

Central tolerance

Refers to elimination of self-reactive T cells and B cells in the central lymphoid organs

Peripheral tolerance

Occurs from deletion or inactivation of autoreactive T cells or B cells that escaped elimination in the central lymphoid organs

Humoral (B-cell) tolerance

Loss of self-tolerance that occurs due to development of autoantibodies

1. Characteristic of many autoimmune disorders (for example, hyperthyroidism in Graves disease)

2. Several mechanisms to filter autoreactive B cells out of the B-cell population:

   1. Clonal deletion of immature B cells in the bone marrow

   2. Deletion of autoreactive B cells in the spleen or lymph nodes

   3. Functional inactivation

   4. Receptor editing

Receptor editing

Process that changes the specificity of a B-cell receptor when an autoantigen is encountered

Cellular (T-cell) tolerance

Involves deletion of self-reactive T-cells in the thymus

1. T cells develop from bone marrow–derived progenitor cells that migrate to the thymus, where they encounter self-peptides bound to MHC molecules.

Positive selection

Process by which T cells that display the host’s MHC antigens and T-cell receptors for a nonself-antigen are permitted to mature in the thymus

Negative selection

Process by which T cells that have a high affinity for host cells are sorted out and undergo apoptosis (cell death)

1. Requires the presence of autoantigens, many of which are not present in the thymus

2. Result is that some self-reactive T cells may escape the thymus

peripheral

Several _____ mechanisms help control the responsiveness of self-reactive T cells that escape the thymus:

1. Host antigens may not be available in the appropriate immunologic form or may be separated from the T cells.

2. Autoreactive T cells may encounter their corresponding antigens in the absence of costimulatory signals necessary for their activation.

3. Apoptotic receptors on the surface of autoreactive T cells may bind with a soluble membrane messenger molecule, activating the cells’ death program.

4. Suppressor T cells are also believed to play a role in peripheral T-cell tolerance, although the mechanisms by which they do so are unclear.

Autoimmunity

Caused by a loss of self-tolerance.

1. The exact mechanism by which this occurs is largely unknown, although genetics, environmental factors, and even gender may play a role.

Heredity (genetics), environment

___ and ____ are the two primary factors believed to cause autoimmune disease.

____ factors increase the incidence and severity of autoimmune diseases.

1. The molecular basis for this association is unknown.

2. Because autoimmunity does not develop in all individuals with a genetic predisposition, it is likely that some sort of trigger event precipitates the altered immune state.

3. Potential triggers include viruses, microorganisms, chemical substances, or self-antigens that were previously hidden from the immune system.

___ factors are often involved in the pathogenesis of autoimmune diseases.

1. The exact role of these factors is largely unknown.

2. Proposed mechanisms include the breakdown of T-cell anergy (failure to recognize antigens), the release of sequestered antigens, molecular mimicry, and superantigens.

assays

The criteria for determining an autoimmune disorder is determination that immunologic findings are not caused by another condition, along with the lack of other identified causes for the disorder.

1. Specific diagnosis of autoimmune disease currently based on clinical findings and serological testing

• Basis for serologic _____ is the demonstration of antibodies that are directed against tissue antigens or cellular components.

• ___ involve diluting an individual’s serum and allowing it to react with an antigen-coated surface.

• For most assays, the serum is serially diluted until it no longer produces a reaction (called a positive titer).

2. Treatment is based on the tissue or organ that is affected, the effector mechanism involved, and the magnitude and chronicity of effector processes.

• Immunosuppressive drugs and corticosteroids may be used to arrest or reverse the course of the disease.

• In severe cases, plasmapheresis may be used to purge autoreactive cells.

• Researchers are seeking to develop vaccines that protect against various autoimmune disorders.

Systemic lupus erythematosus (SLE)

Chronic autoimmune disease that causes generalized inflammation

1. Affects skin, joints, kidneys, pleura, pericardium, and brain

2. Characterized by fatigue, rashes, arthritis, and fever

3. Usually involves periods of exacerbation followed by periods of remission

Etiology and pathogenesis of SLE

Clearly multifocal but not fully known

1. More common in women and most often manifests between the ages of 15 and 44

2. Affects African Americans and people of Asian descent more than individuals of other races and ethnicities

3. A drug-induced form of SLE can be caused by the body’s overreaction in response to certain medications.

4. Most manifestations of SLE are mediated both directly and indirectly by antibody formation and creation of immune complexes (IC).

5. Pathogenic potential of IC varies, depending on several variables:

• Characteristic of the antibody

• Nature of the antigen

• Ability of the IC to be solubilized by the complement and bond to the complement receptor on red blood cells

• Rate at which IC are cleared by immunoglobulin receptors on monocytes or macrophages in the liver and spleen

Constitutional symptoms

Symptoms experienced by most individuals with SLE at some point after diagnosis

1. Fatigue

2. Fever

3. Myalgia

4. Weight change

5. Butterfly rash: Erythema in a malar distribution over the cheeks and nose

1. Other manifestations vary and may involve one or more of the major body systems.

Butterfly Rash

Erythema in a malar distribution over the cheeks and nose

Dignosis and Treatment of SLE

___ of SLE is based on clinical judgment after other diagnoses have been ruled out.

1. In the absence of diagnostic criteria, clinicians use the SLE classification criteria to identify salient clinical manifestations.

2. Serologic data is useful because certain antibodies are highly correlated with SLE.

Treatment has multiple focuses:

1. Ensuring long-term survival

2. Achieving lowest possible disease activity

3. Preventing organ damage

4. Minimizing drug toxicity

5. Improving quality of life

6. Educating patients about disease management

Treatment is individualized depending on patient preference and a the rheumatologist that will judge based on clinical manifestations, disease activity and severity, and existing comorbidities.

1. Nonpharmacological measures may include:

• Protection from sunlight

• Maintaining adequate nutrition

• Exercise

• Smoking cessation

• Receiving appropriate immunizations

Tissue Transplant

• Becoming an increasingly common treatment for diseases. The most common type is allograft

• In the normal state the immune system is “self-tolerant” but it will attack anything “non-self”. 

• Because no two humans have identical antigen makeup (except identical twins), the immune system will attack an allograft (the transplant organ)- causing rejection.  

• Rejection is the immune system response to the foreign antigens and cells in the allograft. Involve the humoral and cell mediated response. It will eventually result in destruction of the transplant tissue (inflammation leading to necrosis). 

• Rejection risk can be reduced by seeking donor tissues which are close as possible to the antigen makeup of the recipient. This is accomplished by human leukocyte antigens (HLAs) matching. 

• Risk can be further reduced with immune suppressor therapy – medication which reduce the activity or effectiveness of the immune system. A careful balance must be maintained to prevent opportunistic infection in the patient with reduced immune defense.  

Allograft

tissue or an organ from a different individual is applied to the patient

Immunodeficiency disorders

Involve abnormalities in B-lymphocyte, T-lymphocyte, phagocytic, and/or complement-related immune function.

1. These disorders have negative effects on innate immunity, adaptive immunity, maintenance of self-tolerance, and cancer cell surveillance.

2. May be secondary or primary

Secondary (acquired) immunodeficiency disorders

Result from a variety of internal and external factors

1. More common than primary disorders

2. Common contributors:

• Aging

• Stress

• Nutritional deficiencies

• Selected malignancies

• Infection

• Immunosuppressive treatment modalities

2. Most common cause overall is nutritional deficiency.

3. Most common life-threatening cause is acquired immunodeficiency syndrome (AIDS).

Primary immunodeficiency disorders

Result from genetic mutations, the majority of which are inherited

1. More than 250 known disorders

2. Generally rare, although more frequent in certain populations

3. Most commonly reported disorders:

• Selective IgA deficiency

• X-linked agammaglobulinemia

• Hypogammaglobulinemia

• Common variable immunodeficiency

• Specific antibody deficiency

• Transient hypogammaglobulinemia of infancy

• Severe combined immunodeficiency (“bubble boy” disease)

Immunodeficiency

Concepts Related to ____

1. Nutritional status

2. Cellular regulation

3. Infection

4. Oxygenation

5. Fluid and electrolyte balance

6. Sexuality

Acquired immunodeficiency syndrome (AIDS)

Condition characterized by severe immunodeficiency, opportunistic infections, and/or malignancies

1. First identified in 1981

2. Responsible for more than 39 million deaths worldwide

3. Despite treatment advances, remains a leading cause of death in developing nations.

Human immunodeficiency virus (HIV)

Retrovirus that infects key immune cells and induces defects in cellular and humoral immunity

1. Causative agent of AIDS

2. Two identified strains:

3. Believed to have evolved from a related virus that affected chimpanzees

1. Infection encompasses a continuum of clinical and immunological manifestations, from asymptomatic infection to full-blown AIDS.

   1. Disease progression is highly variable.

   2. Variability correlates with individual differences in efficiency of immune response, as well as genetic differences in the infecting viral subtype.

2. Antiretroviral drugs have greatly prolonged the survival of people with ___, but current treatments cannot fully eradicate the virus from infected individuals

HIV-1 ; HIV-2

Two strains of HIV

1. ___ Responsible for most infections 

2. ___ Genetically similar to HIV-1 but less pathogenic

body fluids ; sexual contact

HIV is transmitted through the exchange of ___ ___ (not including tears or saliva).

Primary mode of transmission is via ____ ___

1. Most efficient transmission modes are penile–anal and penile–vaginal intercourse.

2. Presence of genital ulcers increases the risk of transmission.

3. Infected males are more likely than infected females to transmit the virus to their partners.

4. Antiretroviral therapy may reduce the risk of transmission to uninfected partners.

Transmission can also occur via exchange of blood through transfusion, injection drug use, or occupational needlestick injuries.

1. Risk of transmission via transfusion has been very low (1 in 1–1.5 million) since the introduction of enhanced testing procedures in the 1990s.

2. Risk of needlestick transmission is about 0.3%.

   1. Transmission is most likely when the wound is deep, there is visible blood on the instrument, and the source person has a high viral titer.

   2. Postexposure prophylaxis should be instituted as soon as possible.

Transmission of HIV

There are five requirements for __ ___ ___ from an infected host to an uninfected individual:

1. There must be an infected host.

2. There must be infectious viral particles in a body fluid.

3. There must be a bolus of infectious particles.

4. Infectious particles must encounter target cells in an uninfected individual.

5. Infected cells must escape clearance from the immune system.

Epdemiology of HIV

Globally, an estimated 35 million people are HIV-positive, but an estimated 19 million are not aware they are infected.

1. HIV/AIDS is the world’s leading cause of death among adults aged 15–59.

2. Nearly 80% of all HIV/AIDS-related deaths occur in sub-Saharan Africa.

3. In North America, an estimated 1.3 million people were HIV-positive and 20,000 AIDS-related deaths were reported in 2014.

   1. Medication advances have greatly increased life expectancy and reduced death rates in North America.

   2. African Americans account for a disproportionate number of new HIV cases.

Vertical transmission

Transmission of HIV from mother to infant

1. Accounts for more than 300,000 new infections each year, mostly in developing countries

2. Can occur in different ways at different times:

   1. Prepartally via transplacental passage

   2. Intrapartally via infant’s exposure to mother’s blood and vaginal secretions

   3. Postpartally via ingestion of breast milk

3. Antiretroviral therapy can reduce the risk of ____ by 90%.

Retrovirus ; Lentivirus

HIV can be categorized as both a ___ and ___

1. ____ Virus with genetic material composed of RNA

2. ___ Virus that infects cells of the immune system and causes immunodeficiency

HIV Structure

1. Virus is spherical.

2. Outer surface is made of phospholipids and glycoproteins.

3. Inner surface is lined with matrix proteins that stabilize the virus.

4. Center of virus is a cone-shaped core that contains several important components:

• Two strands of RNA

• Reverse transcriptase enzymes necessary for viral replication

HIV Genes

1. Has 9 genes composed of approximately 10,000 nucleotides.

2. Three genes code for structural and enzymatic proteins.

3. Rest of genome codes for regulatory proteins, including those necessary for viral replication.

HIV-1 Subtypes

Can be categorized into four phylogenetic groups: 

1. M (major) group

2. O (outlier) group

3. N (non-M/non-O) group

4. P group

Group M accounts for most HIV infections worldwide and has 11 different subtypes.

Groups O, N, and P have been identified only in African countries.

The genetic diversity of HIV has been a major limitation to vaccine development.

Tropism

Ability to infect target cells

1. HIV differs in its ____:

• All isolates are capable of infecting CD4⁺ T lymphocytes.

• Some isolates are capable of infecting macrophages, while others are only capable of infecting T lymphocytes.

Classification of HIV Disease

1. Centers for Disease Control and Prevention (CDC) system for classifying severity of infection is based on age-specific CD4⁺ T-lymphocyte count or CD4⁺ T-lymphocyte percentage of total lymphocytes.

Stages range from 0 to 3.

1. Criteria for stage 0 are sequential test results suggestive of early infection.

2. If criteria for stage 0 are met, then stage is 0 regardless of criteria for other stages.

3. If criteria for stage 0 are not met and a stage-3 defining opportunistic illness has been diagnosed, then the stage is 3 regardless of CD4⁺ cell count.

4. If criteria for stage 0 are not met and criteria for other stages are unavailable, then the stage is classified as unknown.

HIV Lifecycle

Can be broken into seven stages:

1. Binding

2. Fusion

3. Reverse transcription

4. Integration

5. Transcription and translation

6. Assembly

7. Budding

CD4

HIV infects cells that have the ____ receptor on their surface.

1. ___ cells that are susceptible to infection include helper T cells, monocytes/macrophages, dendritic cells, and brain microglial cells.

2. HIV uses chemokine receptors as coreceptors to gain entry into target cells.

1. Two chemokine receptors serve as coreceptors for HIV:

• CXCR4: Mediates infection by T tropic viral isolates

• CCR5: Mediates infection by M tropic viral isolates

3. Individuals who fail to express the CCR5 receptor are resistant to infection with M tropic isolates.

4. Individuals who are heterozygous for this mutation are susceptible to infection with M tropic isolates but show slower disease progression.

Chemokine receptors

G-protein–coupled receptors whose activation mediates leukocyte extravasation and migration

CXCR4 ; CCR5

Two chemokine receptors serve as coreceptors for HIV:

• ____ Mediates infection by T tropic viral isolates

• ____ Mediates infection by M tropic viral isolates

gp120

Attachment, Fusion, and Entry

1. The ____ envelope protein in HIV is responsible for the virus’s attachment to target cells

Viral attachment involves two binding events:

1. Binding of __ to the CD4 molecule

• This causes conformational changes in ___ that permit the subsequent binding event.

2. Binding of the chemokine receptor

• This triggers conformational changes that expose a gp41 region called the fusion peptide.

• The fusion peptide is inserted into the host cell membrane.

• The gp41 protein folds back and pulls the viral envelope and host cell membranes together, resulting in their fusion.

Following fusion, the virus sheds its protein coat and releases its contents into the target cell’s cytoplasm

Reverse transcriptase

Viral polymerase that generates two copies of DNA using the viral RNA as a template

DNA strand synthesis does not proceed from one end of the viral RNA template to the other.

1. Instead, the DNA is partially transcribed at one end of the RNA template, then jumps to the other end of the template.

2. Transcription continues in the opposite direction until a complete strand is formed

Long terminal repeats (LTRs)

Structures that flank the end of each DNA copy and contain binding sites for viral proteins that regulate replication

1. Viral DNA and an enzyme called integrase migrate to the cell nucleus via nuclear pores.

2. Integrase links the LTRs into the host DNA.

• Provirus: Term used to describe the integrated viral DNA

• Viral genes are now part of the host cell’s chromosomes and will replicate whenever the host cell replicates.

Provirus

Term used to describe the integrated viral DNA

AIDS

HIV infection may be primary, chronic, or advanced

____ is the most advanced form of infection

Primary HIV Infection

Nonspecific, acute syndrome that occurs 2–4 weeks after viral infection and lasts for 1–2 weeks

1. Experienced by 40–90% of individuals with HIV

2. Common signs and symptoms:

• Fever

• Fatigue

• Headache

• Lymphadenopathy (enlarged lymph nodes)

• Arthralgias (pain in multiple joints)

• Maculopapular rash on face and trunk

3. Viral titers are typically very high (between 10⁵ and 10⁶ copies per mL) during this period.

• Concentrations are especially elevated in plasma and genital secretions.

• As a result, infected individuals are highly contagious.

4. Transient decrease in CD4⁺ T-lymphocyte count also occurs.

5. Concludes with dramatic decrease in viral load and partial rebound in CD4⁺ T-lymphocyte count

Seroconversion

Process by which neutralizing antibodies appear, generally within a few weeks to a few months following infection

Window period

Time between infection and seroconversion

1. During the___ __, HIV testing will detect only HIV antibodies, which may lead to false negatives.

Chronic HIV Infection

1. After acute HIV infection subsides, most individuals show no clinical manifestations for several years, even without treatment

2. Still, HIV actively replicates and there is an intense reduction in the half-life of circulating CD4⁺ T lymphocytes

3. Average duration of the asymptomatic period is 10 years, with considerable variability.

4. Several factors influence the duration of the asymptomatic period:

• Age of host (older age = faster progression)

• Behavioral factors (e.g., smoking, poor nutrition, depression, unprotected anal intercourse = faster progression)

• Genetic variation in CD8⁺ T lymphocytes (involved in immune response to HIV)

Symptomatic Disease

1. HIV-related conditions develop as CH4⁺ T-lymphocyte counts decline.

2. Early conditions (e.g., headache, fatigue) are generally non–life-threatening.

3. Conditions become more severe over time and may include fever, night sweats, diarrhea, and mucocutaneous abnormalities.

4. Most advanced stage of infection is AIDS.

• Characterized by severe immunodeficiency (CD4 T-lymphocyte count < 200 cells/mm³), opportunistic infections, and/or malignancies

• Highly active antiretroviral therapy (introduced in 1995) has dramatically improved survival rates.

Antiretroviral therapy (ART)

Cornerstone of HIV treatment

• Typically involves combination of at least 3 medications that reduce viral replication

Highly active antiretroviral therapy (HAART)

Use of a combination of antiretroviral drugs to help reduce viral resistance to medication

Opportunistic ; malignancies ; Neuropathic

Several types of conditions are commonly associated with HIV/AIDS:

1. ____ infections

2. Certain __

3. ____ disorders

Opportunistic infection (OI)

Infection that occurs with increased frequency or greater severity due to the host’s weakened or compromised immune system

1. Causative organisms usually do not cause illness in healthy individuals.

2. Common OIs associated with HIV include cytomegalovirus diseases and tuberculosis.

Cytomegalovirus (CMV)

Double-stranded DNA virus carried by 60% of U.S. population

• Found in blood, saliva, semen, cervical secretions, and urine

1. Normally, the immune system inhibits ___ replication.

2. In individuals with severe immunosuppression, active replication can occur

• Virus is disseminated to target tissues such as the retina, gut, lungs, and central nervous system.

• ____ retinitis is the most common ____ infection among AIDS patients.

3. Treated with valganciclovir, which terminates elongation of viral DNA

OI

Tuberculosis (TB)

Acid-fast bacillus transmitted through aerosolized droplets

1. Upon inhalation, __ bacilli are transported to the pulmonary alveoli

2. Within the alveoli, the bacilli are ingested and walled off in granulomas by alveolar macrophages

1. Although HIV infection does not confer increased risk of acquiring __, it does increase the risk of activation of latent disease

2. Because __ is the leading cause of death among people with HIV, annual tuberculin testing is recommended

3. Several types of drugs are used in the treatment of TB:

• First-line drugs: Isoniazid and rifamycin in combination with pyrazinamide and ethambutol

• Second-line drugs: Fluoroquinolones and aminoglycosides

4. Emerging strains of __ are resistant to first- and/or second-line drugs and may be treated with bedaquiline fumarate.

Granuloma

Mass of fused macrophages that sequester persistent infectious agents to prevent their activation and dissemination

Malignancies

Several types of ____ are associated with HIV/AIDS.

Examples include Kaposi sarcoma and certain forms of lymphoma

Kaposi sarcoma (KS)

Most common AIDS-associated malignancy

1. Caused by human herpesvirus 8

2. Exact site of tumor initiation is unknown but may be mesenchymal cells, smooth muscle cells, and/or fibroblasts.

3. Tumors generally manifest in skin but can also develop in oral cavity, gut, lymph nodes, brain, and visceral organs

4. Lesions present as localized or disseminated plaques and/or nodules that are brown, red, or purple.

5. Course of disease is highly variable, and lesions may regress with HAART-induced immunoreconstitution.

6. Possible therapies include intralesional injections of vinblastine, radiation therapy, and systemic treatment with cytotoxic agents.

AIDS-related lymphoma

Heterogeneous collection of B-cell malignancies that occur in extranodal sites, including the central nervous system, GI tract, and liver

• May also manifest as pleural effusions in pleural, pericardial, and peritoneal cavities

• Typically occurs when CD4⁺ T-lymphocyte count is < 50 cells/mm³

1. Caused by Epstein-Barr virus (EBV)

• Also known as human herpesvirus 4

• Carried by 90–95% of people in the United-States

• Immunocompetent people show no symptoms of infection.

In individuals with HIV:

• T-cell dysfunction leads to uncontrolled EBV replication and dysregulated B-cell proliferative responses.

• Expanded pool of B cells can become infected with EBV and undergo genetic changes that lead to malignancy.

1. Treatment is chemotherapy in combination with HAART.

Other Conditions

HIV is associated with numerous neurologic and metabolic alterations.

Examples include distal symmetric polyneuropathy and HIV-associated lipodystrophy syndrome

Distal symmetric polyneuropathy (DSP)

Form of HIV-associated peripheral neuropathy that affects up to 50% of infected persons

1. Is a sensory axonal neuropathy that involves the toes, soles of feet, and in some cases, fingers and hands

2. Most common manifestations are absent or diminished ankle jerks and diminished sensation in the distal lower extremities.

• Patients may also experience aching, stabbing, burning, or tingling in affected regions

• Usually begins in lower extremities but may eventually affect upper extremities

3. Can result from HIV infection itself or from treatment with neurotoxic drugs

• Pathogenesis likely involves production of pro-inflammatory and neurotoxic factors by activated immune cells in the peripheral nerves.

• Nerve biopsy usually reveals degeneration of axons in both myelinated and unmyelinated fibers.

4. Pain is poorly responsive to opioids or nonsteroidal anti-inflammatory drugs.

5. Antidepressants, anticonvulsants, and corticosteroids provide partial relief and are the treatment of choice.

HIV-associated lipodystrophy syndrome (HALS)

Collection of morphologic and metabolic abnormalities including insulin resistance, glucose intolerance, dyslipidemia, and fat redistribution (e.g., truncal obesity and peripheral wasting)

1. Approximately 50% of individuals with HIV exhibit at least one ___-associated abnormality

2. Etiology not fully understood but may involve several factors

• HAART-induced adipocyte inflammation

• Oxidative stress

• Macrophage infiltration

• Mitochondrial toxicity

• Impaired adipocyte function

Classical pathway ; Alternate pathway ; complement

____ stimulated by antigen-antibody complex

___ stimulated by microorganism cell wall

___ made of about 20 proteins (made by liver) that are activated when exposed to bacterial antigens

interferon

released by viral infected cells which stimulate neghboring cells to produce antiviral proteins (host dies)

IgM

fixes complement, often 1st produced. Powerful aggutinagen (IG)

IgA

(Ig) secreted into tears and colostrum, protects body surfaces

IgD

(Ig) bidning site on B cells

IgG

(Ig) activates complement found in plasma

IgE

(Ig) binds to mast cells and basophils, stimulates inflammation

Active Natural, Active artifical, Passive Natural, Passive artificial

Types of Humoral Immunity
____: infection, contact with pathogen
____: vaccine, dead or attenuated pathogens
_____: antibodies pass from mother to fetus via placenta, or infant in her milk
____: injectin of immune serum (gamma globulin)