Autoimmune Diseases
These are a group of disease where antibodies  (or CMI) are produced against self antigens, causing disease process.

Normally one's immune competent cells do not react against one's own tissues. This is due to self tolerance acquired during embryogenesis. Any antigen encountered at that stage is recognized as self and the clone of cells capable of forming the corresponding antibody is suppressed.

Mechanism of autoimmunity

(1) Alteration of antigen

-Physicochemical denaturation by UV light, drugs etc. e.g. SLE.
- Native protein may turn antigenic  when a foreign hapten combines with it, e.g. Haemolytic anemia with Alpha methyl dopa.

(2) Cross reaction: Antibody produced against foreign antigen may cross react with native protein because of partial similarity e.g. Rheumatic fever.

(3) Exposure of sequestered antigens: Antigens not normally exposed to immune competent cells are not accepted as self as tolerance has not been developed to them. e.g. thyroglobulin, lens protein, sperms.

(4) Breakdown of tolerance : 
Emergence of forbidden clones (due to neoplasia of immune system as in lymphomas and lymphocytic leukaemia)
Loss of suppressor T cells as in old age and CMI defects

Autoimmunity may be
Organ specific.
Non organ specific (multisystemic)

I. Organ specific

(1) Hemolytic anaemia:

Warm or cold antibodies (active at 37° C or at colder temperature)
They may lyse the RBC by complement activation or coat them and make them vulnerable to phagocytosis

(2) Hashimoto's thyroiditis:
 
Antibodies to thyroglobulin and microsomal antigens.
Cell mediated immunity.
Leads to chronic. destructive thyroiditis.

(3) Pernicious anemia

Antibodies to gastric parietal cells and to intrinsic factor.

2. Non organ specific.

Lesions are seen in more than one system but principally affect blood vessels and
connective tissue (collagen diseases).

1. Systemic lupus erythematosus  (SLE). Antibodies to varied antigens are seen. Hence it is possible that there is abnormal reactivity of the immune system in self recognition.

Antibodies have been demonstrated against:

Nuclear material (antinuclear I antibodies) including DNA. nucleoprotein etc. Anti nuclear antibodies are demonstrated by LE cell test.
Cytoplasmic organelles- mitochondria, rib osomes, Iysosomes.
Blood constituents like RBC, WBC. platelets, coagulation factors.

Mechanism. Immune complexes of body proteins and auto antibodies deposit in various
organs and cause damage as in type III hypersensitivity

Organs involved
Skin- basal dissolution and collagen degeneration with fibrinoid vasculitis.
Heart- pancarditis.
Kidneys- glomerulonephritis of focal, diffuse or membranous type 
Joints- arthritis. 
Spleen- perisplenitis and vascular thickening (onion skin).
Lymph nodes- focal necrosis and follicular hyperplasia.
Vasculitis in other organs like liver, central or peripheral nervous system etc,

2. Polyarteritis nodosa. Remittant .disseminated necrotising vasculitis of small and medium sized arteries

Mechanism :- Not definitely known. Proposed immune reaction to exogenous or auto antigens 

Lesion : Focal panarteritis- a segment of vessel is involved. There is fibrinoid necrosis
with initially acute and later chronic inflammatory cells. This may result in haemorrhage
and aneurysm.

Organs involved. No organ or tissue is exempt but commonly involved organs are :
- Kidneys.
- Heart.
- Spleen.
- GIT

3. Rheumatoid arthritis. A disease primarily of females in young adult life. 

Antibodies
- Rheumatoid factor (An IgM antibody to self IgG)
- Antinuclear antibodies in 20% patients.

Lesions

- Arthritis which may progress on to a crippling deformity.
- Arteritis in various organs- heart, GIT, muscles.
- Pleuritis and fibrosing alveolitis.
- Amyloidosis is an important complication.

4. Sjogren's  Syndrome. This is constituted by 

- Kerato conjunctivitis sicca
-Xerostomia
-Rheumatoid arthritis. 

Antibodies

- Rheumatoid factor
- Antinuclear factors (70%).
- Other antibodies like antithyroid, complement fixing Ab etc
- Functional defects in lymphocytes. There is a higher incidence of lymphoma

5. Scleroderma (Progressive systemic sclerosis)
Inflammation and progressive sclerosis of connective tissue of skin and viscera.

Antibodies

- Antinuclear antibodies.
- Rheumatoid factor. .
- Defect is cell mediated.

lesions

Skin- depigmentation, sclerotic atrophy followed by cakinosis-claw fingers and mask face.
Joints-synovitis with fibrosis
Muscles- myositis.
GIT- diffuse fibrous replacement of muscularis resulting in hypomotility and malabsorption
Kidneys changes as in SLE and necrotising vasculitis.
Lungs – fibrosing alveolitis.
Vasculitis in any organ or tissue.

6.Wegener’s granulomatosis. A complex of:
Necrotising lesions in upper respiratory tract.
Disseminated necrotising vasculitis.
Focal or diffuse glomerulitis.

Mechanism. Not known. It is classed with  autoimmune diseases because of the vasculitis  resembling other immune based disorders.
 

Q Fever

An acute disease caused by Coxiella burnetii (Rickettsia burnetii) and characterized by sudden onset of fever, headache, malaise, and interstitial pneumonitis.

Symptoms and Signs

The incubation period varies from 9 to 28 days and averages 18 to 21 days. Onset is abrupt, with fever, severe headache, chills, severe malaise, myalgia, and, often, chest pains. Fever may rise to 40° C (104° F) and persist for 1 to > 3 wk. Unlike other rickettsial diseases, Q fever is not associated with a cutaneous exanthem. A nonproductive cough and x-ray evidence of pneumonitis often develop during the 2nd wk of illness.

In severe cases, lobar consolidation usually occurs, and the gross appearance of the lungs may resemble that of bacterial pneumonia

About 1/3 of patients with protracted Q fever develop hepatitis, characterized by fever, malaise, hepatomegaly with right upper abdominal pain, and possibly jaundice. Liver biopsy specimens show diffuse granulomatous changes, and C. burnetii may be identified by immunofluorescence.

Multiple sclerosis
a. A demyelinating disease that primarily affects myelin (i.e. white matter). This affects the conduction of electrical impulses along the axons of nerves. Areas of demyelination are known as plaques.
b. The most common demyelinating disease.
c. Onset of disease usually occurs between ages 20 and 50; slightly more common in women.
d. Disease can affect any neuron in the central nervous system, including the brainstem and spinal cord. The optic nerve (vision) is commonly affected.

PRIMARY LYMPHEDEMA  
can occur as:
1- A congenital defect, resulting from lymphatic agenesis or hypoplasia.  

2- Secondary or obstructive lymphedema  
- blockage of a previously normal lymphatic; e.g. Malignant tumors 
- Surgical procedures that remove lymph nodes 
- Postirradiation  
- Fibrosis 
- Filariasis 
- Postinflammatory thrombosis and scarring 

Aneurysm

An aneurysm is a localized abnormal dilation of a blood vessel or the heart

Types:
1. True aneurysm - it involves all three layers of the arterial wall (intima, media, and adventitia) or the attenuated wall of the heart.
 e.g. Atherosclerotic, syphilitic, and congenital aneurysms, and ventricular aneurysms that follow transmural myocardial infarctions. 

2 False aneurysm 
(also called pseudo-aneurysm) is a breach in the vascular wall leading to an extravascular hematoma that freely communicates with the intravascular space ("pulsating hematoma"). 
E.g. ventricular ruptures after MI that are contained by a pericardial adhesion
E.g. a leak at the junction of a vascular graft with a natural artery.

Aneurysms are classified by macroscopic shape and size 
Saccular aneurysms 

spherical outpouchings (involving only a portion of the vessel wall, and often contain thrombi. 

Fusiform aneurysms

diffuse, circumferential dilation of a long vascular segment; 

they vary in diameter and length and can involve extensive portions of the aortic arch, abdominal aorta, or even the iliacs.

Aortic Aneurysm 

The two most important causes are: 

1- atherosclerosis : the most common cause 
It causes thinning and weakening of the media. The intimal plaques compress the underlying media and also compromise nutrient and waste diffusion from the vascular lumen into the arterial wall. The media consequently undergoes degeneration and necrosis, thus allowing the dilation of the vessel 

2- cystic medial degeneration of the arterial media. E.g. Marfan syndrome.

3- Other causes include: trauma, congenital defects (e.g., berry aneurysms), infections (mycotic aneurysms), systemic diseases, such as vasculitis.

Mycotic  Aneurysm :  
Infection of a major artery that weakens its wall is called a mycotic aneurysm

possible complications: thrombosis and rupture. 

It can originate from: 
(1) embolization of a septic thrombus, usually as a complication of infective endocarditis 
(2) extension of an adjacent suppurative process; 
(3) circulating organisms directly infecting the arterial wall 

Mycotic AAAs are atherosclerotic lesions infected by lodging of circulating microorganisms in the wall 

- e.g.  bacteremia from a primary Salmonella gastroenteritis. 

Abdominal Aortic  Aneurysm

Atherosclerotic aneurysms occur most frequently in the abdominal aorta ,the common iliac arteries, the arch, and descending parts of the thoracic aorta can also be involved 

Pathogenesis 

AAA occurs more frequently in men and rarely develops before age 50. 

Atherosclerosis is a major cause of AAA 

 hereditary defects in structural components of the aorta (e.g., defective fibrillin production in Marfan disease affects elastic tissue synthesis) 
 
 Morphology :
  Usually positioned below the renal arteries and above the bifurcation of the aorta 
  
  AAA can be saccular or fusiform 
  
  as large as 15 cm in diameter, and as long as 25 cm. 
  
  Microscopically: atherosclerosis with destruction and thinning of the underlying aortic media 
  
  the aneurysm frequently contains a laminated mural thrombus
  
  Syphilitic Aneurysm 
  
  Caused by The spirochetes T. pallidum 
  
  Tertiary stage of syphilis can cause obliterative endarteritis of the involve small vessels in any part of the body, including the vasa vasorum of the aorta 
  
  This results in ischemic medial injury, leading to aneurysmal dilation of the aorta and aortic annulus, and eventually valvular insufficiency. 
  
  valvular insufficiency and massive volume overload lead to hypertrophy of the left ventricle. The greatly enlarged hearts are sometimes called "cor bovinum" (cow's heart).
  
  CLINICAL CONSEQUENCES
  
  1.  Rupture → massive potentially fatal hemorrhage 
  2. Obstruction of downstream vessel → tissue ischemic injury
  3. Embolism → from atheroma or mural thrombus 
  4. Impingement and compression on an adjacent structure 
  5. Presentation as an abdominal mass 

 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)