Alterations in Immune Function

Alterations in Immune Function

Course Overview

• Instructor: C Constantin, PhD, RNC

Hypersensitivity Topics

• Immune Deficiencies

  • Primary Immunodeficiencies

  • Secondary (Acquired) Immunodeficiencies

• HIV/AIDS

• Countermeasures to Infection

Hypersensitivity

Specific Objectives

• Describe and compare the four types of hypersensitivity reactions.

• Describe how an individual becomes sensitized to an allergen in type I hypersensitivity reactions.

Hypersensitivity Reactions Definition

• Hypersensitivity: An altered immunologic response to an antigen that leads to disease or damage to the host.

• Classification methods:

  • Source of Antigen:

  • Allergy

  • Autoimmunity

  • Alloimmunity* (response to antigens from members of the same species)

  • Mechanism Causing Disease:

  • Type I

  • Type II

  • Type III

  • Type IV

Examples of Hypersensitivity and Their Characteristics

• Type I:

  • Mechanism: IgE-mediated reaction.

  • Rate of Development: Immediate.

  • Principal Effector Cells: Mast cells.

  • Antibody Involvement: No.

  • Disorders: Seasonal allergic rhinitis, latex allergy.

• Type II:

  • Mechanism: Tissue-specific reaction.

  • Rate of Development: Immediate.

  • Principal Effector Cells: Macrophages in tissues.

  • Antibody Involvement: Frequently.

  • Disorders: Autoimmune thrombocytopenic purpura, Graves' disease.

• Type III:

  • Mechanism: Immune complex-mediated reaction.

  • Rate of Development: Delayed.

  • Principal Effector Cells: None.

  • Antibody Involvement: Yes.

  • Disorders: Systemic lupus erythematosus.

• Type IV:

  • Mechanism: Cell-mediated reaction.

  • Rate of Development: Delayed.

  • Principal Effector Cells: Lymphocytes,

    macrophages.

  • Antibody Involvement: No.

  • Disorders: Contact sensitivity to poison ivy and metals.

Sensitization in Hypersensitivity Reactions

• Sensitization requires exposure to a particular antigen that leads to both primary and secondary immune responses.

• The sensitization process can be rapid (after just one exposure) or require several exposures.

  • Example: Poison Ivy Reaction, PPD skin test.

Timing of Immune Responses

• A person is considered sensitized when they possess sufficient antibodies or T cells to cause a measurable reaction upon re-exposure to the antigen.

• Hypersensitivity reactions may be:

  • Immediate: Minutes to a few hours after exposure.

  • Delayed: Several hours; maximum severity occurs days after re-exposure.

Types of Hypersensitivity Reactions

• Type I:

  • IgE-mediated reactions leading to anaphylaxis or allergic responses.

  • Examples: Bee stings, drug reactions, asthma, latex allergy.

• Type II:

  • Tissue-specific antibody-mediated reactions causing destruction of target cells.

  • Conditions: Hemolytic disease of the newborn, autoimmune hemolytic anemia.

• Type III:

  • Immune complexes cause tissue inflammation and damage.

  • Conditions: Serum sickness, rheumatoid arthritis.

• Type IV:

  • T-cell mediated responses that are delayed.

  • Conditions: Tuberculosis skin test, poison ivy reactions.

Anaphylaxis

• Definition: Most rapid and severe immediate hypersensitivity reaction (Type I).

• Timeframe: Occurs within minutes of re-exposure.

• Types: Systemic (widespread) and cutaneous (localized).

• Symptoms of systemic anaphylaxis may include:

  • Itching, erythema, headaches, vomiting, abdominal cramps, diarrhea, and breathing difficulties.

  • Severe cases can involve bronchial smooth muscle contraction, laryngeal edema, and vascular collapse.

Type II Hypersensitivity

• Description: Antibody-mediated destruction of target cells, usually occurs within 15-30 minutes of exposure.

• Mechanism: Antibodies bind to specific tissue antigens marking cells for destruction, mediated by complement system and phagocytosis.

• Symptoms vary based on the affected tissue.

• Examples of Type II Reactions:

  • ABO transfusion reactions.

  • Hemolytic disease of the newborn.

  • Hyperacute graft rejection.

  • Graves' disease.

  • Myasthenia gravis.

  • Type 1 diabetes mellitus.

Type III Hypersensitivity

• Mechanism: Antibody-antigen complexes deposit in tissues and activate the complement system causing inflammation and destruction.

• Etiology: Occurs when immune and phagocytic systems fail to effectively clear these complexes.

• Conditions: Chronic infection that persists as a source of circulating antigens.

• Examples:

  • Serum sickness.

  • Immune complex glomerulonephritis.

  • Arthus reaction.

Type IV Hypersensitivity

• Description: T-cell mediated (no antibody production) resulting in delayed hypersensitivity.

• Timeframe: Reacts slowly (~24 hours) and may last for 14 days.

• Mechanism: T-cells react with altered or foreign cells, leading to inflammation.

• Principal effector cells: Lymphocytes and macrophages.

• Examples:

  • Tuberculin skin test, contact dermatitis (poison ivy), transplant rejection.

Immune Deficiencies

Types of Immune Deficiencies

• Primary Immunodeficiencies (PID):

  • Congenital; genetic defects leading to functional deficiencies.

  • Clinical hallmark: Tendency to develop unusual or recurrent severe infections.

• Secondary Immunodeficiencies:

  • More common; induced by conditions such as cancer, stress, malnutrition, or acquired immunodeficiency (e.g., HIV/AIDS).

Primary Immunodeficiency Disorders

• Definition: Congenital immune deficiencies caused by genetic defects affecting immunity.

• Common types:

  • B cell deficiencies.

  • T cell deficiencies.

  • Combined T and B cell deficiencies.

  • Phagocyte deficiencies.

  • Complement deficiencies.

• Untreated, can lead to frequent and life-threatening infections.

Examples of Primary Immunodeficiencies

• X-Linked Agammaglobulinemia (Bruton's Disease).

• Severe Combined Immunodeficiency (SCID): Lack of both B and T lymphocyte function, severe infection susceptibility.

• Selective IgA Deficiency (fairly common).

Acquired Immunodeficiency Syndrome (AIDS)

• Definition: Secondary immune deficiency caused by the human immunodeficiency virus (HIV).

• Characteristics:

  • Blood borne RNA virus present in body fluids.

  • Transmission routes: Blood products, IV drug use, sexual activity, maternal-child.

• HIV infects and depletes T helper cells (CD4+), increasing susceptibility to infections and malignancies.

• Statistics:

  • Worldwide incidence (2013): 35.3 million individuals.

  • United States incidence (2012): approximately 49,000 individuals.

Pathogenesis of HIV/AIDS

• Definition: Retrovirus with RNA genetic material.

• Mechanism: Uses reverse transcriptase to convert RNA into double-stranded DNA, thus integrating with the host genome.

Human Immunodeficiency Virus (HIV) Structure and Function

• Structure: gp120 protein binds to CD4 on helper T cells leading to their destruction.

• Normal CD4+ count ranges from $800$ to $1,000$ cells/mm³.

• HIV typically reverses CD4/CD8 ratio.

Clinical Manifestations of HIV/AIDS

• Stage Definitions:

  • Serologically negative: no antibodies.

  • Serologically positive but asymptomatic: presence of antibodies but no symptoms.

  • AIDS stage: defined when CD4+ cells fall below $200$ cells/mm³ and benchmark clinical conditions arise.

• AIDS-defining conditions: include opportunistic infections such as.

  • Pneumocystis jiroveci pneumonia (PCP).

  • Mycobacterium avium complex (MAC).

  • Mycobacterium tuberculosis.

  • Cytomegalovirus (CMV).

  • Kaposi's sarcoma.

  • Candidiasis in respiratory areas.

CD4+ Cell Count and Associated Risks

• Above $500$ CD4+ cells/mm³: Low infection risk; promote good health practices.

• $200-500$ CD4+ cells/mm³: Risk for shingles, thrush, and minor opportunistic infections.

• $50-200$ CD4+ cells/mm³: Increased risk for serious opportunistic infections; preventative treatment indicated.

• Below $50$ CD4+ cells/mm³: High risk for severe opportunistic infections; continued preventative medications recommended.

Treatment of HIV/AIDS

• Treatment involves taking antiviral medications to slow HIV progression.

• Antiretroviral Therapy (ART): Combination of three or more drugs offered to optimize treatment outcomes.

• Components include:

  • Reverse transcriptase inhibitors.

  • Protease inhibitors.

  • Integrase inhibitors.

  • Fusion inhibitors.

  • CCR5 antagonists.

• Not a cure, but significantly lowers mortality rates.

Worksheet

Immunologic Dysfunction Worksheet

1.     Describe what is meant by a hypersensitivity reaction.

A hypersensitivity reaction is when the immune system overreacts to something harmless or misidentifies the body’s own cells as harmful, causing tissue damage and disease instead of protection.

🧬 Detailed Pathophysiology Breakdown

What It Means

• Normally, the immune system protects us by recognizing and destroying harmful invaders (like bacteria, viruses, or toxins).

• In hypersensitivity, the immune system responds inappropriately — either too strongly or against the wrong target.

• This exaggerated response leads to collateral damage: inflammation, cell destruction, or dysfunction of normal tissues.

Why It Happens

1. Sensitization phase

   • On first exposure to an antigen (like pollen, food, or even self-antigens), the immune system “remembers” it.

   • Antibodies (IgE, IgG, IgM) or T cells are primed to react the next time.

2. Re-exposure phase

   • When the antigen reappears, the immune system launches a stronger, faster attack.

   • Instead of helping, this attack damages normal tissues.

Types (Gell & Coombs Classification)

• Type I (IgE-mediated): Allergies, asthma, anaphylaxis. Mast cells release histamine → swelling, itching, bronchospasm.

  • ** on slide: basophils also stimulated; Mast cells are connective tissue and basophils are in the blood.

• Type II (Cytotoxic): Antibodies attack specific cells (e.g., mismatched blood transfusion, Graves disease).

  • She mentioned: remember GRAVES disease, and that Type 2 leads to destruction of cell or altered function of the cell.

• Type III (Immune complex): Antigen-antibody complexes deposit in tissues → inflammation (e.g., lupus, glomerulonephritis).

• Type IV (T-cell mediated): Delayed reaction, no antibodies. T cells cause tissue damage (e.g., TB skin test, poison ivy).

Clinical Significance

• Hypersensitivity explains allergies, autoimmune diseases, and transplant rejection.

• The key problem is immune misidentification: the body thinks harmless antigens or its own cells are dangerous.

• Symptoms range from mild (rash, sneezing) to severe (anaphylaxis, organ damage).

✨ Easy Analogy

Think of the immune system as a security guard:

• Normally, it attacks intruders.

• In hypersensitivity, the guard panics and attacks friendly visitors or even the building itself, causing damage.

✅ Key Point for Exams: Hypersensitivity = exaggerated or misdirected immune response → tissue injury and disease.

2.     Describe the 4 types of hypersensitivity reactions and give an example of each one.

🧬 Four Types of Hypersensitivity Reactions

✨ Easy Memory Hook

• Type I = Immediate (IgE, Allergies)

• Type II = “It’s on the cell” (antibody attacks tissue)

• Type III = “Immune Complexes clog” (deposit in tissues)

• Type IV = “Delayed T-cell” (cell-mediated, no antibodies)

✅ Exam Key Point: Types I–III are antibody-mediated, Type IV is T-cell mediated.

3.     What is a clinical sign that an individual has a primary immunodeficiency? Which cells are affected when a person has a primary immunodeficiency?

🧬 Primary Immunodeficiency

Clinical Sign

·       The hallmark sign is recurrent, unusual, or severe infections that don’t respond normally to treatment.

·       These infections often begin in early childhood (before age 2) and may involve unusual organisms or repeated infections in the same sites (ears, sinuses, lungs, skin).

·       Example: a child with repeated pneumonia, ear infections, or thrush despite antibiotics.

Why? Because the immune system is missing or defective from birth (genetic defect), the body cannot mount normal defenses → infections keep coming back.

Cells Affected

Primary immunodeficiencies can involve any major immune cell type, depending on the genetic defect:

·       B cells (humoral immunity) → ↓ antibodies → recurrent bacterial infections (e.g., X-linked agammaglobulinemia).

·       T cells (cell-mediated immunity) → ↓ cytotoxic/helper function → viral, fungal, opportunistic infections.

·       Combined T & B cell defects → severe combined immunodeficiency (SCID, “boy-in-the-bubble”).

·       Phagocytes → impaired ability to engulf/kill pathogens → chronic bacterial infections.

·       Complement proteins → defective opsonization/lysis → recurrent Neisseria infections.

Why? Each immune cell type has a specialized role. If one is missing, the “defense team” is incomplete → pathogens slip through.

✨ Key Exam Point

·       Clinical sign: recurrent, severe, or unusual infections (especially in young children).

·       Cells affected: can be B cells, T cells, both, phagocytes, or complement proteins, depending on the genetic defect.

4.     What can cause secondary immunodeficiency?

🧬 Secondary (Acquired) Immunodeficiency

Definition

·       Unlike primary immunodeficiency (genetic, present from birth), secondary immunodeficiency develops later in life due to external factors that weaken the immune system.

·       It is much more common than primary forms.

Causes (and the “Why”)

1.     Infections

o   Example: HIV/AIDS → virus destroys CD4+ T helper cells.

o   Why? Loss of T cells cripples both humoral and cell-mediated immunity.

2.     Cancer

o   Leukemia, lymphoma, or bone marrow cancers.

o   Why? Malignant cells crowd out normal immune cells → reduced production/function.

3.     Medications/Drugs

o   Chemotherapy, radiation, immunosuppressants, corticosteroids.

o   Why? These treatments kill rapidly dividing cells, including immune cells, or suppress immune activity.

4.     Poor Nutrition/Malnutrition

o   Protein-calorie malnutrition, vitamin/mineral deficiencies (zinc, iron).

o   Why? Nutrients are required for lymphocyte development and antibody production.

5.     Stress/Neuroendocrine factors

o   Chronic stress → ↑ cortisol.

o   Why? Cortisol suppresses lymphocyte activity and inflammation.

6.     Normal Physiologic Changes

o   Aging → gradual decline in immune function (“immunosenescence”).

o   Why? Bone marrow and thymus activity decrease, fewer naïve T cells produced.

✨ Key Exam Point

·       Secondary immunodeficiency = acquired later in life due to infection, disease, drugs, nutrition, stress, or aging.

·       Why? These factors either destroy immune cells, suppress their function, or prevent their production.

5.     Describe how the human immunodeficiency virus (HIV) is transmitted. How does HIV cause disease?  

🧬 Transmission of HIV

HIV is a blood-borne RNA virus found in body fluids. It is transmitted when infected fluids come into direct contact with mucous membranes or the bloodstream.

Main routes:

·       Sexual contact (heterosexual or homosexual) → virus enters through genital/rectal mucosa.

·       Blood exposure → transfusions (rare now), needle sharing, IV drug use.

·       Mother-to-child → during pregnancy, birth, or breastfeeding.

·       Healthcare exposure → accidental needle sticks.

Why? HIV is fragile outside the body but survives in blood and certain fluids. Transmission requires direct fluid-to-blood/mucosa contact.

🧬 How HIV Causes Disease

1.     Entry into cells

o   HIV has a surface protein (gp120) that binds specifically to CD4 receptors on T helper cells.

o   It also needs co-receptors (CCR5 or CXCR4) to enter.

o   On slide she mentioned on EXAM: Structure – gp120 protein binds to the CD4 molecule found primarily on surface of helper Tcells

1.     Destroys CD4 + Th cells.

2.     Replication

o   HIV is a retrovirus → it carries RNA and uses reverse transcriptase to convert RNA → DNA.

o   Viral DNA integrates into host genome → host cell becomes a “virus factory.”

3.     Destruction of CD4+ T cells

o   Infected T helper cells are destroyed directly or undergo apoptosis.

o   Over time, CD4 count drops (normal ~800–1000 cells/mm³ → AIDS <200 cells/mm³).

4.     Immune system collapse

o   Without T helper cells, both cell-mediated immunity (T cells) and humoral immunity (B cells/antibodies)fail.

o   Body becomes vulnerable to opportunistic infections (PCP pneumonia, CMV, TB, candidiasis) and cancers (Kaposi’s sarcoma, lymphoma).

Why? HIV targets the “commanders” of the immune system (CD4+ T cells). When commanders are gone, the rest of the immune army cannot coordinate defense → infections and malignancies take over.

✨ Key Exam Points

·       Transmission: blood, sexual contact, mother-to-child, needle exposure.

·       Pathophysiology: HIV binds CD4 → enters cells → reverse transcriptase → integrates DNA → destroys T helper cells → immune collapse.

·       Result: Opportunistic infections and cancers define AIDS.

6.     What is the criteria for assigning a diagnosis of AIDS? List some of the “AIDS-defining conditions”.

🧬 Criteria for AIDS Diagnosis

A person is diagnosed with AIDS (Acquired Immunodeficiency Syndrome) when:

1.     CD4+ T helper cell count < 200 cells/mm³ (normal is ~800–1000).

o   Why? HIV destroys CD4+ cells, which are the “commanders” of the immune system. Below 200, the immune system can no longer coordinate defense.

2.     Presence of AIDS-defining conditions (opportunistic infections or cancers).

o   Why? These infections/cancers only occur when the immune system is severely weakened.

3.     Positive HIV test (antibodies or viral RNA detected).

🧬 AIDS-Defining Conditions

These are illnesses that signal the immune system is critically compromised:

·       Opportunistic infections

o   Pneumocystis jiroveci pneumonia (PCP)

o   Mycobacterium avium complex (MAC)

o   Mycobacterium tuberculosis (TB)

o   Cytomegalovirus (CMV) infection

o   Candidiasis (esophagus, bronchi, trachea, lungs)

·       Cancers

o   Kaposi’s sarcoma (vascular tumor linked to HHV-8)

o   Non-Hodgkin lymphoma

o   Invasive cervical cancer

·       Other severe conditions

o   Wasting syndrome (unexplained weight loss >10% with diarrhea/weakness/fever)

o   Recurrent bacterial infections

✨ Key Exam Point

·       Diagnosis of AIDS = HIV infection + CD4 <200 + AIDS-defining condition.

·       Why? At this stage, the immune system is so damaged that infections and cancers normally controlled by immunity can now take hold.
On slide in Red: CD4 (T helper) cells need to be <200 cells/mm3 AND they have to have various clinical conditions and lab results.

7.     Drugs used to treat HIV infection target different aspects of how a virus infects a cell and replicates. Name the type of drugs used in Antiretroviral therapy (ART).

🧬 Antiretroviral Therapy (ART) Drug Classes

✨ Key Exam Point

·       ART = combination therapy (usually 3+ drugs from different classes).

·       Why? HIV mutates quickly. Using multiple drug classes prevents resistance and attacks the virus at multiple stages: entry → reverse transcription → integration → protein processing.

✅ Summary for your study guide: ART drugs include reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, fusion inhibitors, and CCR5 antagonists. Each targets a different step in HIV’s life cycle to stop replication.