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

Drug induced thrombocytopenia (especially sedormid).

Agranulocytosis due to sensitivity to some drugs.

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
  • Drug induced vasculitis.
  • 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)

TUBERCULOSIS

A chronic, recurrent infection, most commonly in the lungs

Etiology, Epidemiology, and Incidence

TB refers only to disease caused by Mycobacterium tuberculosis, M. bovis, or M. africanum. Other mycobacteria cause diseases similar to TB

Pathogenesis

The stages of TB are primary or initial infection, latent or dormant infection, and recrudescent or adult-type TB.

Primary TB may become active at any age, producing clinical TB in any organ, most often the apical area of the lung but also the kidney, long bones, vertebrae, lymph nodes, and other sites. Often, activation occurs within 1 to 2 yr of initial infection, but may be delayed years or decades and activate after onset of diabetes mellitus, during periods of stress, after treatment with corticosteroids or other immunosuppressants, in adolescence, or in later life (> 70 yr of age), but especially after HIV infection. The initial infection leaves nodular scars in the apices of one or both lungs, called Simon foci, which are the most common seeds for later active TB. The frequency of activation seems unaffected by calcified scars of primary infection (Ghon foci) or by residual calcified hilar lymph nodes. Subtotal gastrectomy and silicosis also predispose to development of active TB.

Pulmonary Tuberculosis

recrudescent disease occurs in nodular scars in the apex of one or both lungs (Simon foci) and may spread through the bronchi to other portions

Recrudescence may occur while a primary focus of TB is still healing but is more often delayed until some other disease facilitates reactivation of the infection.

In an immunocompetent person whose tuberculin test is positive (>= 10 mm), exposure to TB rarely results in a new infection, because T-lymphocyte immunity controls small, exogenous inocula promptly and completely.

Symptoms and Signs:

Cough is the most common symptom,

At first, it is minimally productive of yellow or green mucus, usually on rising in the morning, but becomes more productive as the disease progresses

Dyspnea may result from rupture of the lung or from a pleural effusion caused by a vigorous inflammatory reaction

Hilar lymphadenopathy is the most common finding in children. due to lymphatic drainage from a small lesion, usually located in the best ventilated portions of the lung (lower and middle lobes), where most of the inhaled organisms are carried.

swelling of the nodes is common

Untreated infection may progress to miliary TB or tuberculous meningitis and, if long neglected, rarely may lead to pulmonary cavitation.

TB in the elderly presents special problems. Long-dormant infection may reactivate, most commonly in the lung but sometimes in the brain or a kidney, long bone, vertebra, lymph node, or anywhere that bacilli were seeded during the primary infection earlier in life

TB may develop when infection in an old calcific lymph node reactivates and leaks caseous material into a lobar or segmental bronchus, causing a pneumonia that persists despite broad-spectrum antibiotic therapy.

With HIV infection, progression to clinical TB is much more common and rapid.

HIV also reduces both inflammatory reaction and cavitation of pulmonary lesions. As a result, a patient's chest x-ray may be normal, even though AFB are present in sufficient numbers to show on a sputum smear. Recrudescent TB is almost always indicated when such an infection develops while the CD4⁺ T-lymphocyte count is >= 200/µL. By contrast, the diagnosis is usually infection by M. avium-intracellulare if the CD4+ count is < 50. The latter is noninfectious for others.

Pleural TB develops when a small subpleural pulmonary lesion ruptures, extruding caseous material into the pleural space. The most common type, serous exudate, results from rupture of a pimple-sized lesion of primary TB and contains very few organisms.

Tuberculous empyema with or without bronchopleural fistula is caused by a more massive contamination of the pleural space resulting from rupture of a large tuberculous lesion. Such a rupture allows air to escape and collapse the lung. Either type requires prompt drainage of pus and initiation of multiple drug therapy

Extrapulmonary Tuberculosis

Remote tuberculous lesions can be considered as metastases from the primary site in the lung, comparable to metastases from a primary neoplasm. TB of the tonsils, lymph nodes, abdominal organs, bones, and joints were once commonly caused by ingestion of milk infected with M. bovis.

GENITOURINARY TUBERCULOSIS

The kidney is one of the most common sites for extrapulmonary (metastatic) TB. Often after decades of dormancy, a small cortical focus may enlarge and destroy a large part of the renal parenchyma.

Salpingo-oophoritis can be a complication of primary TB after onset of menarche, when the fallopian tubes become vascular.

TUBERCULOUS MENINGITIS

Spread of TB to the subarachnoid space may occur as part of generalized dissemination through the bloodstream or from a superficial tubercle in the brain

Symptoms are fever (temperature rising to 38.3° C [101° F]), unremitting headache, nausea, and drowsiness, which may progress to stupor and coma. Stiff neck (Brudzinski's sign) and straight leg raising are inconstant but are helpful signs, if present. Stages of tuberculous meningitis are (1) clear sensorium with abnormal CSF, (2) drowsiness or stupor with focal neurologic signs, and (3) coma. Likelihood that CNS defects will become permanent increases with the stage. Symptoms may progress suddenly if the lesion causes thrombosis of a major cerebral vessel.

Diagnosis is made by examining CSF. The most helpful CSF findings include a glucose level < 1/2 that in the serum and an elevated protein level along with a pleocytosis, largely of lymphocytes. Examination of CSF by PCR is most helpful, rapid, and highly specific.

MILIARY TUBERCULOSIS

When a tuberculous lesion leaks into a blood vessel, massive dissemination of organisms may occur, causing millions of 1- to 3-mm metastatic lesions. Such spread, named miliary because the lesions resemble millet seeds, is most common in children < 4 yr and in the elderly.

TUBERCULOUS LYMPHADENITIS

In primary infection with M. tuberculosis, the infection spreads from the infected site in the lung to the hilar nodes. If the inoculum is not too large, other nodes generally are not involved. However, if the infection is not controlled, other nodes in the superior mediastinum may become involved. If organisms reach the thoracic duct, general dissemination may occur. From the supraclavicular area, nodes in the anterior cervical chain may be inoculated, thus sowing the seeds for tuberculous lymphadenitis at a later time. Most infected nodes heal, but the organisms may lie dormant and viable for years or decades and can again multiply and produce active disease.

Neuroblastoma and Related Neoplasms
Neuroblastoma is the second most common solid malignancy of childhood after brain tumors, accounting for up to10% of all pediatric neoplasms. They are most common during the first 5 years of life. Neuroblastomas may occur anywhere along the sympathetic nervous system and occasionally within the brain. Most neuroblastomas are sporadic. Spontaneous regression and spontaneous- or therapy-induced maturation are their unique features.  

Gross features
- The adrenal medulla is the commonest site of neuroblastomas. The remainder occur along the sympathetic chain, mostly in the paravertebral region of the abdomen and posterior mediastinum. 
- They range in size from minute nodules to large masses weighing more than 1 kg. 
- Some tumors are delineated by a fibrous pseudo-capsule, but others invade surrounding structures, including the kidneys, renal vein, vena cava, and the aorta. 
- Sectioning shows soft, gray-tan, brain-like tissue. Areas of necrosis, cystic softening, and hemorrhage may be present in large tumors. 

Microscopic features
- Neuroblastomas are composed of small, primitive-appearing neuroblasts with dark nuclei & scant cytoplasm, g rowing in solid sheets.  
- The background consists of light pinkish fibrillary material corresponding to neuritic processes of the primitive cells. 
- Typically, rosettes can be found in which the tumor cells are concentrically arranged about a central space filled with the fibrillary neurites.
- Supporting features include include immunochemical detection of neuron-specific enolase and ultrastructural demonstration of small, membrane-bound, cytoplasmic catecholamine-containing secretory granules.
- Some neoplasms show signs of maturation, either spontaneous or therapy-induced. Larger ganglion-like cells having more abundant cytoplasm with large vesicular nuclei and prominent nucleoli may be found in tumors admixed with primitive neuroblasts (ganglioneuroblastoma). Further maturation leads to tumors containing many mature ganglion-like cells in the absence of residual neuroblasts (ganglioneuroma). 

Many factors influence prognosis, but the most important are the stage of the tumor and the age of the patient. Children below 1 year of age have a much more favorable outlook than do older children at a comparable stage of disease. 

Miscroscopic features are also an independent prognostic factor; evidence of gangliocytic differentiation is indicative of a "favorable" histology. Amplification of the MYCN oncogene in neuroblastomas is a molecular event that has profound impact on prognosis. The greater the number of copies, the worse is the prognosis. MYCN amplification is currently the most important genetic abnormality used in risk stratification of neuroblastic tumors. 

About 90% of neuroblastomas produce catecholamines (as pheochromocytomas), which are an important diagnostic feature (i.e., elevated blood levels of catecholamines and elevated urine levels of catecholamine metabolites such as vanillylmandelic acid [VMA] and homovanillic acid [HVA]). 

Plasma Cell Pathology

A. Multiple myeloma

1. Plasma cell neoplasm that results in the proliferation of monoclonal plasma cells. These tumor cells produce nonfunctional immunoglobulins.

2. Laboratory findings include:

a. Monoclonal IgG spike.

b. Bence-Jones proteins found in urine.

3. Radiographic findings: characteristic “punched-out” radiolucencies in bones.

Respiratory Viral Diseases

Respiratory viral infections cause acute local and systemic illnesses. The common cold, influenza, pharyngitis, laryngitis (including croup), and tracheobronchitis are common.

An acute, usually afebrile, viral infection of the respiratory tract, with inflammation in any or all airways, including the nose, paranasal sinuses, throat, larynx, and sometimes the trachea and bronchi.

Etiology and Epidemiology

Picornaviruses, especially rhinoviruses and certain echoviruses and coxsackieviruses, cause the common cold. About 30 to 50% of all colds are caused by one of the > 100 serotypes of rhinoviruses.

Symptoms and Signs

Clinical symptoms and signs are nonspecific.

After an incubation period of 24 to 72 h, onset is abrupt, with a burning sensation in the nose or throat, followed by sneezing, rhinorrhea, and malaise.

Characteristically, fever is not present, particularly with a rhinovirus or coronavirus. Pharyngitis usually develops early; laryngitis and tracheobronchitis vary by person and causative agent. Nasal secretions are watery and profuse during the first days, but become more mucoid and purulent.

Cough is usually mild but often lasts into the 2nd wk.

Lysosomal (lipid) storage diseases
- Genetic transmission: autosomal recessive.
- This group of diseases is characterized by a deficiency of a particular lysosomal enzyme. This results in an accumulation of the metabolite, which would have otherwise been degraded by the presence of normal levels of this specific enzyme.

Diseases include:
Gaucher’s disease
(1) Deficient enzyme: glucocerebrosidase.
(2) Metabolite that accumulates: glucocerebroside.
(3) Important cells affected: macrophages.

Tay-Sachs disease
(1) Deficient enzyme: hexosaminidase A.
(2) Metabolite that accumulates: GM2 ganglioside.
(3) Important cells affected: neurons.
(4) Symptoms include motor and mental deterioration, blindness, and dementia.
(5) Common in the Ashkenazi Jews.

Niemann-Pick disease
(1) Deficient enzyme: sphingomyelinase.
(2) Metabolite that accumulates: sphingomyelin.
(3) Important cells affected: neurons.