IMMUNO PATHOLOGY
Abnormalities of immune reactions are of 3 main groups
- Hypersensitivity,
- Immuno deficiency,
- Auto immunity.
Hypersensitivity (ALLERGY)
This is an exaggerated or altered immune response resulting in adverse effects

They are classified into 4 main types.

I. Type I-(reaginic, anaphylactic). This is mediated by cytophylic Ig E antibodies, which get bound to mast cells. On re-exposure, the Ag-Ab reaction occurs on the mast cell surface releasing histamine.

Clinical  situations

I. Systemic anaphylaxis, presenting with bronchospasm oedema hypertension, and even death.
2. Local (atopic) allergy.
- Allergic rhinitis (hay fever)
- Asthma
- Urticaria.
- Food allergies.

2. Type II. (cytotoxic). Antibody combines with antigen present on-cell surface. The antigen may be naturally present on the surface or an extrinsic substance (e.g.drug) attached to cell surface.

The cell is then destroyed by complement mediated lysis (C89) or phagocytosis of the antibody coated cell. 

Clinical situations

- Haemolytic anemia.
- Transfusion reaction
- Auto immune haemolytic anemia.
- Haemolysis due to some drugs like Alpha methyl dopa

2. Drug induced thrombocytopenia (especially sedormid).
3 Agranulocytosis due to sensitivity to some drugs.
4 Goodpasture’s syndrome-glomermerulonephritis due to anti basement membrane antibodies.

3. Type III. (Immune complex disease). Circulating immune complexes especially small soluble complexes tend to deposit in tissues especially kidney, joints, heart and arteries.

These then cause clumping of platelets with subsequent release of histamine. and serotonin resulting in increased permeability. Also, complement activation occurs which being chemotactic results in aggregation of polymorphs and necrotising vasculitis due to release of lysosmal enzymes

Clinical situations

- Serum sickness.
- Immune complex glomerulonephritis.
- Systemic lupus erythematosus.
- Allergic alveolitis.
- Immune based vasculitis like
    o    Drug induced vasculitis.
    o    Henoch – Schonlein purpura

4. Type IV. (Cell mediated). The sensitized lymphocytes may cause damage by cytotoxicity or by lymphokines and secondarily involving macrophages in the reaction.

Clinical situations

I. Caseation necrosis in tuberculosis.
2. Contact dermatitis to
    - Metals.
    - Rubber.
    - Drugs (topical).
    - Dinitrochlorbenzene (DNCB).
    
5. Type V. (stimulatory) This is classed by some workers separately and by other with cytotoxic type (Type II) with a stimulatory instead of toxic effect

Clinical Situations :
LATS (long acting thyroid stimulator) results in thyrotoxicosis (Grave’s disease)
 

Asthma

Asthma is

(1) An obstructive lung disease characterized by narrowing of the airways.

Inflammation of the airways is a major component of asthma.

(2) Common symptoms are dyspnea, wheezing on expiration, and coughing.

(3) Two types:

(a) Extrinsic (allergic, atopic) asthma

(i) An atopic allergy caused by a type I immediate hypersensitivity immune reaction to an allergen.

(ii) Seen in children, adults.

(b) Intrinsic (nonallergic) asthma

(i) Not caused by an allergic reaction.

(ii) Mostly seen in adults.

The disorder is a chronic inflammatory condition in which the airways develop increased responsiveness to various stimuli, characterized by bronchial hyper-responsiveness, inflammation, increased mucus production, and intermittent airway obstruction.

Signs and symptoms

• The clinical hallmarks of an attack are shortness of breath (dyspnea) and wheezing
• A cough—sometimes producing clear sputum—may also be present
• The onset is often sudden; there is a "sense of constriction" in the chest, breathing becomes difficult, and wheezing occurs
• Signs of an asthmatic episode are wheezing, rapid breathing (tachypnea), prolonged expiration, a rapid heart rate (tachycardia), rhonchous lung sounds (audible through a stethoscope), and over-inflation of the chest.
• During very severe attacks asthma sufferer can turn blue due to lack of oxygen , can experience chest pain or even loss of consciousness, may lead to respiratory arrest and death

Pathophysiology

Bronchoconstriction : asthma is the result of an abnormal immune response in the bronchial airways. The airways of asthmatics are "hypersensitive" to certain triggers, also known as stimuli, these stimuli include allergens, medications , air pollution, early child hood infection, exercise, emotional stress

Bronchial inflammation asthma resulting from an immune response to inhaled allergens—are the best understood of the causal factors. In both asthmatics and non-asthmatics, inhaled allergens that find their way to the inner airways are ingested by a type of cell known as antigen presenting cells These activate an humoral immune response. The humoral immune system produces antibodies against the inhaled allergen. Later, when an asthmatic inhales the same allergen, these antibodies "recognize" it and activate a humoral response. Inflammation results: chemicals are produced that cause the airways to constrict and release more mucus, and the cell-mediated arm of the immune system is activated. The inflammatory response is responsible for the clinical manifestations of an asthma attack

Symptomatic Treatment

Episodes of wheeze and shortness of breath generally respond to inhaled  bronchodilators which work by relaxing the smooth muscle in the walls of the bronchi., More severe episodes may need short courses of inhaled, oral, or intravenous steroids which suppress  inflammation and reduce the swelling of the lining of the airway.

Bronchodilators (usually inhaled)

Short-acting selective  beta2-adrenoceptor agonists(salbutamol, terbutaline)

less selective adrenergic agonists, such as inhaled epinephrine and ephedrine tablets

Antimuscarinics

Systemic steroids

Oxygen to alleviate the hypoxia that is the result of extreme asthma attacks.

If chronic acid indigestion ( GERD) is part of the attack, it is necessary to treat it as well or it will restart the inflammatory process

Preventive Treatment

most effective preventive medication are

Inhaled  corticosteroids

Long-acting beta2-adrenoceptor agonists

Leukotriene modifiers

Mast cell stabilizers

Methylxanthines (theophylline and aminophylline),

Antihistamines, often used to treat allergic symptoms

INFARCTION

Definition : a localized area of ischaemic necrosis in an organ infarcts may be:
Pale :as in
    →    Arterial obstruction.
    →    solid organs.
Red as in
    →    Venous occlusion
    →    Loose tissue.

Morphology
Gross: infarcts are usually wedge shaped the apex towards the occluded vessel They are
separated from the surrounding tissue by an hyperemic inflammatory zone

Microscopic:
- An area of coagulative necrosis with a rim of congested vessels and acute inflammatory infiltration of the tissue .
- The polymorphs ale later replaced by mononuclear cells and granulation tissue.
- With time, scar tissue replaces necrosed tissue.
 

Cardiac tamponade
A. Caused by accumulation of fluid in the pericardium. This severe condition can quickly impair ventricular filling and rapidly lead to  decreased cardiac output and death.

1. Signs and symptoms include:
a. Hypotension.
b. Jugular venous distention.
c. Distant heart sounds.

Hepatitis

Hepatitis viruses—this group of viruses causes hepatitis, a disease affecting the liver.
1. General characteristics of hepatitis.
a. The general presentation of hepatitis is the same regardless of the infecting virus; however, the time and severity of symptoms may differ.
b. Symptoms of hepatitis include fever, anorexia, malaise, nausea, jaundice, and brown-colored urine.
c. Complications of a hepatitis infection include cirrhosis, liver failure, and hepatorenal failure.

THROMBOSIS 
Pathogenesis (called Virchow's triad):
1. Endothelial* Injury ( Heart, Arteries)
2. Stasis
3. Blood Hypercoagulability

- Endothelial cells are special type of cells that cover the inside surface of blood vessels and heart.

CONTRIBUTION OF ENDOTHELIAL CELLS TO COAGULATION

Intact endothelial cells maintain liquid blood flow by: 

1- inhibiting platelet adherence
2- preventing coagulation factor activation
3- lysing blood clots that may form.

Endothelial cells can be stimulated by direct injury or by various cytokines that are produced during inflammation.

Endothelial injury results in:
1- expression of procoagulant proteins (tissue factor and vWF)→ local thrombus formation.
2- exposure of underlying vWF and basement membrane collagen  →  platelet aggregation and thrombus formation. 

RESPONSE OF VASCULAR WALL CELLS TO INJURY( PATHOLOGIC EFFECT OF VASCULAR HEALING) 

Injury to the vessel wall results in a healing response, involving:
- Intimal expansion (proliferating SMCs and newly synthesized ECM). This involves signals from ECs, platelets, and macrophages; and mediators derived from coagulation and complement cascades.

- luminal stenosis & blockage of vascular flow 

Causes of Endothelial injury
1. Valvulitis
2. MI
3. Atherosclerosis
4. Traumatic or inflammatory conditions
5. Increased Blood Pressure
6. Endotoxins
7. Hypercholesterolemia
8. Radiation
9. Smoking 

Stasis

- Stasis is a major factor in venous thrombi
- Normal blood flow is laminar (platelets flow centrally in the vessel lumen, separated from the endothelium by a slower moving clear zone of
plasma)
- Stasis and turbulence cause the followings:

Disuption of normal blood flow 
prevent dilution of activated clotting factor
retard inflow of clotting factor inhibitor
promote endothelial cell injury

Causes of Stasis
1. Atherosclerosis
2. Aneurysms
3. Myocardial Infarction ( Non-cotractile fibers)
4. Mitral valve stenosis (atrial dilation)
5. Hyper viscosity syndromes (PCV and Sickle Cell anemia)

Hypercoagulability
A. Genetic (primary):
- mutations in the factor V gene and the prothrombin gene are the most common
B. Acquired (secondary):
- multifactorial and more complicated 
- causes include: Immobilization, MI, AF, surgery, fracture, burns, Cancer, Prosthetic cardiac valves 

MORPHOLOGY OF THROMBI 

Can develop anywhere in the CVS (e.g., in cardiac chambers,  valves, arteries, veins, or capillaries).

Arterial or cardiac thrombi→ begin at sites of endothelial injury; and are usually superimposed on an atherosclerotic plaque. 

 Venous thrombi → occur at sites of stasis. Most commonly the veins of the lower extremities (90%)

 Thrombi are focally attached to the underlying vascular surface; arterial and venous thrombi both tend to propagate toward the heart.
→ The propagating portion of a thrombus is poorly attached → fragmentation and embolus formation

LINES OF ZAHN

Thrombi can have grossly (and microscopically) apparent laminations called lines of Zahn; these represent pale platelet and fibrin layers alternating with darker erythrocyte-rich layers. 

Such lines are significant in that they represent thrombosis of flowing blood. 

Mural thrombi = Thrombi occurring in heart chambers or in the aortic lumen.

Causes: -Abnormal myocardial contraction (e.g. arrhythmias, dilated cardiomyopathy, or MI) -endomyocardial injury (e.g. myocarditis, catheter trauma)

Vegetations ->Thrombi on heart valves 

1- Bacterial or fungal blood-borne infections - (infective endocarditis,). 

2- Non-bacterial thrombotic endocarditis occur on sterile valves.

Fate of thrombi 

1. Propagation → Thrombi accumulate additional platelets and fibrin, eventually causing vessel obstruction 

2. Embolization → Thrombi dislodge or fragment and are transported elsewhere in the vasculature 

3. Dissolution → Thrombi are removed by fibrinolytic activity (Usually in recent thrombi) 

4. Organization and recanalization → Thrombi induce inflammation and fibrosis. - recanalization (re-establishing some degree of flow) - Organization = ingrowth of endothelial cells, smooth cells and fibroblasts into the fibrin rich thrombus.

5. Superimposed infection (Mycotic aneurysm)

Venous thrombi → most common in veins of the legs 

a. Superficial: e.g. Saphenous veins. - can cause local congestion, swelling, pain, and tenderness along the course of the involved vein, but they rarely embolize

a. Deep: e.g. Popliteal, Femoral and iliac vein. - more serious because they may embolize - can occur with stasis or hypercoagulable states