Module 2

Immune Dysfunction and Pathophysiology of Cellular Injury

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Learning Outcomes
1. How hypoxia causes cellular injury
✅ Less oxygen → Less ATP → Cell can’t work properly
✅ Water and sodium build up → Cell swells
✅ Acid levels rise → Cell functions break down
✅ If not fixed → Cell dies

2. Describe the mechanisms of cellular hypoxic injury

✅ Temporary damage → Cell can recover
✅ Causes: Low oxygen, toxins, mild stress
✅ Swelling, fatty changes, ATP drop
✅ Remove stress → Cell returns to normal

3. Discuss reversible cell injury

✅ Temporary damage → Cell can recover
✅ Causes: Low oxygen, toxins, mild stress
✅ Swelling, fatty changes, ATP drop
✅ Remove stress → Cell returns to normal

4. Discuss irreversible cell injury and relate this to acute disease

✅ Too much damage → Cell cannot recover
✅ Membrane breaks, enzymes leak → Cell death
✅ Happens in heart attacks, strokes, organ failure

5. Describe the aetiology of allergies

✅ Body overreacts to harmless things (dust, pollen, food, meds)
✅ Genetics + environment → Higher allergy risk

6. Describe the clinical manifestation of a patient with Type 1 hypersensitive reaction &
Anaphylaxis
✅ Skin → Itchy, hives, swelling
✅ Lungs → Wheezing, breathing problems
✅ Heart → Fast heartbeat, low blood pressure
✅ Stomach → Nausea, cramps, diarrhea
- Sudden onset of symptoms after allergen exposure.
- Skin: Urticaria (hives), pruritus, flushing, and angioedema.
 - Respiratory: Wheezing, shortness of breath, bronchospasm, and airway obstruction.
- Cardiovascular: Hypotension, tachycardia, and potential circulatory collapse.

7. Describe the pathophysiology of Type 1 hypersensitive reaction & Anaphylaxis

✅ First exposure → Body makes IgE antibodies
✅ Next time → Body releases histamine → Swelling, redness, breathing trouble
✅ Severe reaction → Blood pressure drops → Anaphylactic shock
- Initial exposure to an allergen leads to IgE antibody production.
- Subsequent exposure triggers mast cell degranulation, releasing histamine and
inflammatory mediators.
- Vasodilation, increased vascular permeability, and bronchoconstriction cause systemic
symptoms.
- Severe cases result in anaphylactic shock due to widespread vasodilation and fluid loss.

8. Describe pharmacological and non-pharmacological management of allergies &

anaphylaxis

💊 Pharmacological - Medications:
✅ Epinephrine → reverse anaphylaxis
✅ Antihistamines → Reduces itching & swelling
✅ Steroids → Prevents long-term issues
✅ Inhalers → Helps breathing

🛑 Non-pharmacological:
✅ Avoid triggers (food, dust, pollen)
✅ Allergy shots (to build tolerance)
✅ Patient education on allergy triggers and emergency management.
✅ Medical alert bracelet** (in case of emergency)
✅ Immunotherapy

9. Describe the complications associated with allergies in children

✅ Increased risk of anaphylaxis due to immature immune response.
✅ Asthma → Can get worse over time, leading to chronic respiratory issues.
✅ Growth issues → Food restrictions affect nutrition
✅ Emotional stress → Anxiety, fear of reactions, anxiety, social isolation
✅ Prone to more infections → Weak immune response
 Module Notes
Acute Inflammation

 Main components of innate immunity.

 Inflammation  Rapid, nonspecific protective response to cellular injury in vascularized
tissues.
 Hallmarks of acute inflammation:

 Vasodilation
 Increased vascular permeability
 Diapedesis (cell movement)
 Macroscopic manifestations of inflammation:

 Redness
 Swelling
 Heat
 Pain
 Loss of function of inflamed tissues

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Cellular Components of Inflammation

 Cells involved in inflammatory process:

- Neutrophils, monocytes, macrophages, eosinophils, platelets

 Mast Cells:

 Most important activatpr of inflammatory response

 Initiates inflammation by releasing biochemical mediators

 Release histamine, chemotactic factors cytoplasmic granule and produce

prostaglandins, leukotrienes, initiating inflammation

 Phagocytic Cells:

 Neutrophils and macrophages engulf and destroy microorganisms

 Encloses them in phagocytic vacuoles
 Toxic products and degradative lysosomal enzymes kill and digest the
microorganisms

 Polymorphonuclear neutrophils:

 Main phagocytic cells in early inflammation

 Exit circulation via diapedesis and move to the site by chemotaxis.

 Macrophages:

 Predominant in late inflammation

 Highly phagocytic
 Responsive to cytokines and aid in wound healing.

 Eosinophils:

 Control inflammatory response

 Kill parasitic organisms
  Platelets:

 Involved in clotting to stop bleeding

 Release mediators controlling inflammation

 Phagocytosis:

Process of elimination of pathogens and foreign debris

 Recognition & Attachment – Phagocyte identifies and binds to the pathogen

or debris
 Engulfment – The phagocyte surrounds and engulfs the target
 Containment – of the foreign debris or pathogen inside a vacuole
 Destruction – Toxic products and lysosomal enzymes kill and digest the
pathogen/debris

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Inflammatory Mediators

 Histamine:

- Major vasoactive amine released from mast cells

- It causes:

- constriction of smooth muscles in lungs

- dilation of capillaries

- retraction of endothelial cells lining the capillaries

- which increases vascular permeability

 Chemotactic Factors:

- Released from mast cell granules

- Forms chemical gradient

- Attract inflammatory cells to injury site.

 Leukotrienes:

- Produce histamnie like effect

- Contribute to smooth muscle contraction and increased permeability

 Nitric Oxide:

- Released from endothelium

 - Causes vasodilation and suppresses mast cell release.

 Prostaglandins:

- Increase vascular permeability, neutrophil chemotaxis, and pain

- Direct effect on nerves

 Cytokines:

- Mediate responses in both innate and adaptive immunity

- Can be pro-inflammatory or anti-inflammatory (e.g., interleukins, interferons).

 Tumor Necrosis Factor-alpha (TNF-α):

- Induces a multitude of pro-inflammatory effects

- Enhances endothelial cell adhesion

- Hence increas adherence of neutrophils

- Strong mediator of fever.

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Plasma protein systems

Three Plasma Protein Systems:

1. Complement system
2. Coagulation system
3. Kinin system

1. Complement System

 Activated by antigen-antibody reactions (classical pathway) or bacterial

polysaccharides (lectin & alternative pathways)
 Produces biologically active fragments → causes cell lysis
 Biologically potent products:
 C3b (opsonin) → Enhances phagocytosis
 C3a (anaphylatoxins)
 C5a (anaphylatoxins, chemotactic factors) → Promote
inflammation

o Opsonins: coat microorganisms, hence more susceptible to phagocytosis by binding them

more tightly to the phagocyte

2. Coagulation System
 Stops bleeding
  Localises microorganisms
 Provides a meshwork for repair and healing

3. Kinin System
 Key component: Bradykinin

 Increases vascular permeability

 Causes smooth muscle contraction
 Induces pain

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Chronic Inflammation

 Can be a continuation of acute inflammation (lasting ≥2 weeks or longer)

 Characterized by dense infiltration of lymphocytes & macrophages
 Granuloma formation may occur to isolate infection & prevent tissue damage

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Clinical Manifestations of Inflammation

Local manifestation:

 Due to vascular changes (vasodilation & ↑ capillary permeability)

 Symptoms: Redness, heat, swelling, pain.

Functions of vascular changes:

 Dilute toxins from damaged cells/microorganisms.

 Transports plasma proteins & leukocytes to the injury site
 Removes debris & initiates healing & repair

Systemic Effects of Inflammation:

 Fever
 ↑ Circulating leukocytes
 ↑ Plasma proteins (acute phase reactants)

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Wound healing

 Primary intention:
 Healing occurs if minimal tissue loss
 restores original structure & function

 Secondary intention:
  Extensive damage and incapable of regeneration
 leads to scar formation

Phases of wound healing:

1. Reconstructive phase: Wound begins to heal

2. Maturation phase: Healed wound is remodelled

 Dysfunctional wound healing:

 Results from abnormalities in inflammatory or reconstructive phases

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Hypersensitivity Reactions

 Hypersensitivity:
 Inappropriate immune response to self-tissues
 Or directed against beneficial foreign tissues (transfusions/ transplants), or
environmental antigens (allergies)
 Hypersensitivity reactions can be
- Immediate: Develops within seconds/hours
- Delayed: Develops within hours/days

 Anaphylaxis: Severe, rapid, explosive reaction → cardiovascular shock (witin

min)
 Allergens: Antigens triggering allergic responses.

 Types of hypersensitivity:

o Type I (Immediate Hypersensitivity)

 Antigen reacts with IgE on mast cells

 Leads to mast cell degranulation
 Releases histamine and other inflammatory mediators

o Type II (Cytotoxic Hypersensitivity)

 Caused by four mechanisms:

1. Complement-mediated lysis
2. Opsonisation & phagocytosis
3. Antibody-dependent cell-mediated cytotoxicity
4. Modulation of cellular function

o Type III (Immune Complex-Mediated Hypersensitivity)

 Immune complexes form and deposit in target tissues

 Activates complement cascade
 Generates chemotactic fragments → attracts neutrophils → inflammation
 o Type IV (Delayed-Type Hypersensitivity)

 Mediated by sensitised T cells

 Two mechanisms:
1. Direct cytotoxicity – T cells kill target cells
2. Lymphokine release – Activates macrophages and other immune cells

• Allergies can be mediated by any of the four mechanisms of hypersensitivity.

 Clinical manifestations of Allergic Reactions:

 Usually localized to the area of initial intake or contact

o Ingested allergens → GI Gastrointestinal symptoms

o Airborne allergens → Respiratory or skin symptoms
o Contact allergens → Reactions at the site of contact

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Transplantation

 Organ transplantation triggers an immune response

 Rejection types:
o Hyperacute – Immediate rejection
o Acute – Weeks to months post-transplant
o Chronic – Months to years post-transplant

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ABO Blood Group System

 Four blood groups:

- O, A, B, AB.

 Individuals have natural antibodies against foreign ABO antigens in their plasma
 ABO compatibility is crucial for safe transfusions
 Rh system is the second most important blood group system.
 O Rh-negative = Universal donor

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 Autoimmune Diseases

 Autoimmunity  Loss of tolerance to self-antigens

 The immune system attacks the body's own cells.
 Exact cause unknown

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Immune Deficiencies

 Immunodeficiency  Failure of normal immune self-defence function

 Types of immunodeficiencies:

 Primary (congenital) – Genetic defects affecting lymphocyte

development.
 Secondary (acquired) – acquired immunodeficiencies, malnutrition, or
other conditions.

 Clinical Hallmark of immunodeficiencies:

 Frequent, severe, or unusual infections.

 Common infection types:

 Cell-mediated defects → Fungal & viral infections

 Humoral/complement defects → Bacterial infections

 Severe Combined Immunodeficiency (SCID):

 Total lack of T-cell function + Severe (partial or total) lack of B-cell

function
 Defects in B-cell function range from total absence to single
immunoglobulin deficiencies.

 Acquired Immunodeficiencies:

 Caused by external factors: malnutrition, medical therapies, trauma,

infections

 Acquired Immunodeficiency Syndrome (AIDS):

 Caused by HIV (a retrovirus)

 HIV infects & destroys CD4 + (helper T) cells, weakening immunity.

 HIV/AIDS Treatment:
  Antiviral therapy: combination of drugs to control the virus
 Supportive therapy: antibiotics for infections, treatment for
malignancies

Key Terms

 Adenosine Triphosphate (ATP) – Major energy source of the cell.

 Aerobic Respiration – ATP production in the presence of oxygen, yielding large energy

output.

 Anaerobic Respiration – ATP production without oxygen, leading to lactic acid buildup.

 Apoptosis – Programmed cell death, essential for normal tissue function and removal of

damaged cells.

 Cellular Injury – Damage that disrupts normal cellular function.

 Hypoxia – Lack of oxygen at the cellular level, leading to anaerobic respiration and

dysfunction.

 Irreversible Cell Injury – Point of no return where a cell cannot recover and dies.

 Ischaemia – Reduced blood flow to tissues, causing oxygen deprivation.

 Necrosis – Uncontrolled cell death leading to tissue damage.

 Reversible Cell Injury – Cell damage from which recovery is possible.

Cellular Injury
 Causes of Cellular Injury:

 Lack of oxygen (hypoxia)

 Free radicals
 Toxic chemicals
 Infectious agents
 Inflammatory and immune responses
 Genetic factors
 Insufficient nutrients
 Physical trauma
 Injurious physical agents (temperature extremes, atmospheric pressure changes, sunlight,
trauma)

 Hypoxia - most common cause of cellular injury

May occur because of:

 Respiratory diseases (e.g., asthma, airway obstruction, blockage)

 Decrease in haemoglobic (blood loss decreased production of red blood cells – eg;
anemia)
 Cardiovascular diseases (cardiac output is reduced, affecting oxygen transport)

 Ischaemia or reduction in blood flow - most common cause of hypoxia is reduction in

blood supply to the cells

 Ischaemia (restricted blood flow)

caused by:

 Arteriosclerosis  gradual narrowing of arteries

 Thrombosis  complete blockage of arteries

 Thrombus can cause anoxia (total lack of oxygen) - result in infarction (cell death)
within minutes e.g. myocardial infarction or pulmonary embolus.

Mechanisms of Cellular Injury

o Biochemical changes that are important to cell injury are:

 ATP depletion
 oxygen and oxygen-derived free radicals
 intracellular calcium and loss of calcium steady state
Sequence of events leading to cell death:

1. Decreased ATP production

2. Failure of active transport mechanisms (sodium-potassium pump failure)
3. Cellular swelling
4. Pathophysiological processes
5. Lysis of the cell membrane and death

 The initial insult in hypoxic injury is ischaemia (cessation of blood flow into vessels
that supply the cell with oxygen and nutrients)
 Reduced aerobic metabolism decreases ATP production.
 Sustained anaerobic metabolism contributes to cell damage.

Reversible vs Irreversible Cell Injury

o Cell injury occurs if the cell is unable to maintain homeostasis

o Injured cells may recover (reversible injury) or die (irreversible injury).

 Reversible Injury:

 associated with cellular swelling

 accumulation of excessive water in the cell, caused by the failure of transport
mechanisms.
 Increases in intracellular lipid content reversible cell injury

 Irreversible Injury:

 Cells death via apoptosis or necrosis

 Apoptosis:

- process of selective cellular self-destruction

- occurs in normal tissue changes like  skin
- also occurs in pathological tissue changes  elimination of infected cells
with damaged DNA which cannot be repaired

 Necrosis:

- Cellular death leading to cellular dissolution (breaking up of cell)

- Sum of the changes after local cell death
- includes the process of autolysis or cellular self-destruction e.g myocardial
infarction
- 4 Types of necroses:

 Coagulative – Common in heart attacks

 Liquefactive – Seen in infections or brain damage
 Caseous – Occurs in tuberculosis
 Fat – Common in pancreas and breast tissue

- Structural signs indicating irreversible injury and progression to necrosis

are:

 dense clumping

 disruption of genetic material

 disruption of cell and organelle membranes

- Gangrenous Necrosis/gangrene: tissue necrosis caused by hypoxia

and bacterial invasion