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Notes of Pathology (MSc)

Hypersensitivity Reaction

  • Immune activation lead to the production of antibody and T cell response that are generally protective against infections (may cause potential damage to host tissue)
  • An exquisite system of checks and balances optimizes antigen-specific eradication of infectious organisms with only trivial innocent bystander injury.

Types of Hypersensitivity

  • Type I,Disease results from IgE antibody adsorbed on mast cells or basophils when these IgE molecules bind their specific antigen (allergen) , they are triggered to release vasoactive amines and other mediators that in turn affect vascular permiabilityand smooth muscle contraction in various organs.
  • Type II,Disorders are caused by humoral antibodies that bind to fixed tissue or cell surface antigen and cause a pathological process by predisposing cells to phagocytosis or complement –mediated lysis.
  • Type III,Disorders are best thought of as “immune complex disease’’; antibodies bind antigens to from large antigen-antibody complexes that precipitate in various vascular beds and activate complement.

The immune complexes and complement activation fragments also attract neutrophils Ultimately, it is the activated complement and the release of neutrophilic enzymes and other toxic molecules (e.g, oxygen metabolites) that cause the tissue damage in immune complex disease.


  • Type IV, Disorders (also called’’ delayed hypersensitivity’’) are cell-mediated immune responses where antigen-specific T-lymphocytes are the ultimate cause of the cellular and tissue injury.

Type I, Hypersensitivity ( Allergy and Anaphylaxis)


Definition: Immunological reaction, developing withen minutes after combination of an antigen with antibody bound on mast cells or basophils, in already sensitized individuals. Depending upon the portal of entry:

Local reaction (Ag  confined to particular site) that is merely annoying (hay fever, seasonal rhinitis) or severely debilitating (asthma)

  • Systemic: follows parental administration ((bee venom, I/V injection of antisera, hormones, enzymes, drugs) results in systemic anaphylaxis with in minutes of exposure.
  • Examples: Urticaria, bronchoconstriction , vomiting , abdominal cramps, diarrhea)
  • Many localized type I reactions have two well defined phases:

The initial response , characterized by vasodilation vascular leakage , and smooth muscle spasm, usually evident within 5-30 minutes after exposure to an allergen and subsiding by 60 minutes.

A second late phase reaction that sets in 2-8 hrs later and lasts for several days.

The late phase reaction in characterized by more intense infiltrationof tissues with eosinophil and other acute and chronic inflammatory cells as well as by tissue destruction in the form of mucosal epithelial cell damage.


Mast Cells

  • Bone marrow derived cells.
  • Widely distributes in the tissues; they are found predominantly near blood vessels and nerves and in sub epithelial sites.
  • Their sytoplasm contains membrane-bound granules that possess a variety of biologically active mediators.
  • They are activated by cross-linking IgE bound to their surface by high affinity Fc receptors.
  • Mast cells can also be stimulated by complement components C5a and C3a (anaphylatoxins) binding to specific mast cell membrane receptors.
  • Melllitin (present in bee venom), and physical stimuli (e.g, heat, cold, sunlight)
  • Drugs (codeine, morphine)



  • Similar to mast cells in many respect but Are not normally present in tissues.
  • They circulate in blood in extremely smallNumbers and,like other granulocytes, can be recruited to inflammatory sites.

Mechanism underlying  type-1Hypersensitivity

  • First exposure of Ag
  • APC present Ag
  • Recognition of Ag by tcr on th2 cells
  • Th2 release IL-3IL-5 which cause

Recruitment of Eosinophil’s


  • Th2 also release IL-4 which cause differential of igEBcellslgE production
  • igE bind to igE receptors on mast cells
  • 2nd exposure to ag
  • Ag bind to igE previously bound to must cells
  • Multivalent Ag bind to more than one ige

Molecule leading to cross linking of igE FcReceptors

  • Mast cell activation & release of mediators.

Primary Mediators

  • Histamine’the most important mediator causesIncreased vascular permeability ‘ vasodilation’Bronchoconstriction’and increased secretion ofMucus.
  • Adenosine-causes Bronchoconstriction andInhibits platelet aggregation.
  • Chemotactic factor for neutrophils andEosinophils.
  • The other mediators are found in granule matrix_heparin and natural proteases(e.g.,tryptase)_these generate kinins and cleave complementComponents to produce additional chemotactic and inflammatory factors.

      Secondary mediators

  • Lipid mediators

Leukotriene (C4,D4 are vasoactive &spasmogenicWhile B4 chemotactic for NP ‘Ep Monocytes)

Prostaglandin : Bronchospasm & increased mucous Secretion)

PAF (platelet aggregation , release of histamine , Bronchospasm vasodilation , chemotactic)

Ctokines :TNF , IL-1 ,IL -3,4,5,6,

Clinical Manifestations

  • Systemic (parenteral) exposure (bee venom ; penicillin ) results in anaphylaxis within minutes after exposure itching, Urticaria (hives), and skin erythema Profound respiratory difficulty and Hypersecretion of mucus – musculature ofGI tract may be involved with vomiting, Diarrhea ,abdominal cramps- systemic Vasodilation (anaphylactic shock)
  • Local reaction
  • - Route of Ag – skin, ingestion,inhalationGenetically controlled – atopy (familialPredisposition) – cytokine gene on chromosome regulates the expressionof IgE

Milk & food Allergy


  • Jersey cows may become allergic to to their Own milk, if milking is delayed
  • Reaction ranging from mild discomfort with urticariato acuteanaphylaxis About 2% of ingested protein isAbsorbed as peptide fragments large enough to be Recognized as foreign Ag.
  • Allergic inhalant Dermatitis – dogs and Cats

 Type ll Hypersensitivity

(Antibody Dependent)

  • Mediated by antibodies directed againstTarget antigens on the surface of call or Other tissue components
  • The antigens may be normal molecules intrinsicTo cell membranes or extra cellular matrix, or they may be adsorbed exogenousantigens

(e.g, drug metabolites)

1)Complement activation



  1. Complement – Dependent Reaction
  • Ag+Ab reaction involving IgM&IgGcauseActivationofg complement system
  • complement can mediate type II Hypersensitivity via two mechanism:

-Direct lysis


Clinically, antibody-mediated reaction

            Occur in the following situations:

  • Transfusion reactions,wherered cells from an incompatibledonor are destroyed after being coated with recipient antibodiesdirected against the donor’sblood group antigens
  • Erythroblastosisfetalis due to Rhesus antigen incompatibility;

maternal antibodies against Rhin a sensitized Rh negative mother cross the placenta and cause destruction of Rh-positivefetal red cells.


  • Drug reaction, where antibody is directedAgainst a particular drug (or its metabolite)That is nonspecifically adsorbed to cell Surface(hemolysis after penicillinAdministration
  • Pemphigus vulgaris caused by antibodies

Against desmosomal proteins that lead toDisruption of epidermal intercellularJunctions

  1. Antibody-dependent Cell-

Mediated Cytotoxicity (ADCC)

  • This form of antibody – mediatedInjury involves killing via cell

Types that bear receptors for The FC portion of IgG; targets

Coated by antibody are lysedWithout phagocytosis orComplement fixation

  • ADCC may be mediated by a Variety of leukocytes, including Neutrophils, eosinophil’sMacrophages and NK cells .
  • Although, ADCC is typicallymediated by IgGlgG antibodies, in

certain instances (e.g, eosinophil mediated killing of parasites; lgE antibodies are used.

  1. Antibody-Mediated Cellular Dysfunction
  • In some cases, antibodiesDirected against cell surfacereceptors impair or dys-regulatefunction without causing cell injury or inflammation
  • In Myasthenia gravis, antibodiesAgainst acetylcholine receptors in

Motor end-plates of skeletalmuscles impair neuromusculartransmission with resultantweakness.

  • In Graves disease, antibodiesagainst the TSH receptor simulate

thyroid epithelial cellsand result in hyperthyroidism

  • Pemphigus vulgaris

 Type III Hypersensitivity

(Immune Complex-Mediated)

  • Mediated by the deposition of antigen-antibodycomplexes, followed by complement activation and accumulation of polymorphoneuclear leukocytes thatproduce tissue demage.
  • Immune complexes can involve exogenous antigensSuch as bacteria and viruses or endogenous antigenssuch as DNA
  • Ag+Ab complexes may be:
  • Circulating or in situ
  • Exogenous
  • Endogenous
  • Systemic(serum sickness) or local (arthus reaction)


  • 1st phase : Ag+Ab complex formation
  • 2nd phase : deposition of Immune complexes in various tissue
  • 3rd Phase:initiation of an inflammatoryReaction in dispersed sites throughoutBody.

Systemic Immune complex Disease

  • Formation of antigenAntibody complexesIn the circulation
  • Deposition of the Immune complexes in Tissues
  • Initiation ofInflammatory reaction in various sites through out the body
  • Two important factors determine whetherImmune complex formation leads to tissueDeposition and disease:

-Size of Immune complex

  • Very large complexes formed in antibody excess are rapidly

Removed from the circulation by mononuclear phagocyticcells and are there before relatively harmless.

  • The most pathogenic complexes are formed during antigen

Excess and are small are of intermediate size, and are cleared

Less avidly by phagocytosis cells, and therefore circulate

Longer-Status of mononuclear phagocyte system (over load                                      or  dysfunction.

Additional factors


  • Charge of complexes
  • Valency of antigen
  • Avidity of antibody
  • Affinity of the antigen for various tissues
  • Three dimensional architecture of theComplexes
  • Hemodynamics of given vascular bed
  • Morphology :necrotizing vasclitis
  • Swelling & proliferation of mesengial and Endothelial cell
  • Neutrophilic monocyte infiltration
  • Favored site of deposition: Renalglomeruli , joints,skin,heart,small blood vessels

Serum sickness

  • Acute serum sickness is the prototype ofSystemic immune complex disease(injection of horse antitetanus serum)

Local Immune Complex Disease

Localized area of tissue necrosis resulting fromImmune complex vasculitis involving lgG&lgM

Type IV Hypersensitivity

(Cell Mediated)

It is immunologic response to variety of intracellular microbe e.g

Mycobacterium, virus, protozoa,fungi,as well as condition like contact

Dermatitis, graft reiection.

  • Principal mechanism of response to :

- intracellular bacteria (Mycobacterium) and Viruses

-Extra cellular agents-Protozoa, fungi, and parasites

-Contact skin sensitivity(poison ivy)

-Transplant rejection and tumor immunity

  • Reaction mediated by Sensitized T cells

Type IV Hypersensitivity can be subdividedInto

  • Delayed type Hypersensitivity initiated by

CD4+ T cells (tuberculine reaction, granulomatous Inflamation)

  • T-cell mediated cytotoxicity

Granulomatous Inflamation

  • A granuloma is a special type of DTH (Delayed type Hypersensitivity) occurring in the setting of persistent or/and nondegradable antigens
  • The initial perivascular CD4 T –cellInfilterate is progressively replaced by Macrophages over a period of of 2-3 weeks
  • These accumulated macrophages typicallyExhibit morphological evidence ofActivation i.e., they become large, flat, andEosinophilic (denoted epitheliod cells)
  • The epitheliod cells occasionally fuse under the Influence of certain cytokines(e.g., IFN-y) to form multinucleated giant cells
  • A microscopic aggregate of epithliod cells,Typically surrounded by a collar of lymphocytes,Is called granuloma, and the pattern referred to as granulomatous inflammation.
  • Older granulomas develop an enclosing rim of fibroblasts and CT.

Tuberculin reaction

  • A classical example is tuberculin reaction, elicited in an individual already sensitized to tubercle bacillus.
  • 8-12 Hrs after intradermal injection of tuberculin (protein-lipoprotein injection), a local area of erythema and induration appears, reaching a peak (typically 1-2 cm) in 24-72 hrs, and there after subsides.
  • Histologically, the DTH reaction is characterized by the perivascular presence of CD4 cells and to lesser extent macrophages (perivascular cuffing)
  • Local secretion of cytokines by these mononuclear inflammatory cells leads to increased micro vascular permeability , giving rise to dermal edema and fibrin deposition; the latter is main cause of induration in these responses.

The Sequence of events


  • Exposure of individual to tubercle bacilli.
  • CD4 lymphoctes recognize peptide antigens in association with MHC class II antigens on the surface of macrophage or dendritic cells.
  • This process leads to the formation of sensitized CD4 cells of the Th1 type that remain in the circulation for years.

T-Cell-Mediated Cytotoxicity

  • Sensitized CD8 T cells kill antigen-bearing target cells.
  • Class I MHC molecules bind to intracellular viral peptides and present them to CD8 T lymphocytes.
  • The CD8 effector cells, called cytotoxic T lymphocytes play a critical role to virus infections.
  • The lysis of infected cells, before viral replication is completed, leads ultimately to elimination of the infection.
  • It is believed that many tumor associated peptides may also be involved in tumor immunity .
  • Example: Tissue rejection be during tissue transplantation.


“ Reaction of vascularized living tissue to local injury”

Purpose: inflammation is a complicated defensive and protective mechanism of the body against and irritant which involves vascular, cellular as well as local tissue reaction.

In this process the blood flow to the effective area is increased and more blood is poured at the site so as to dilute the irritant, localized its effective or even destroys it.

Causes of inflammation:

1.Pathogenic          organisms.

  1. Chemical poisons.
  2. Mechanical and thermal injury.

4.Immune  Reaction.

Cardinal signs of inflammation:

English         Latin

1.Redness: (Rubor):

Great increase in blood at inflamed area as the result of Hyperima.

2.Swelling   (Tumor):

Mainlydue to Hyperimia.

  1. Heat (Color):

                        At site of inflammation there is increased heat . This also results from the increased blood . flow through area.

  1. Pain (Dolar):

                                    The inflamed are is pain full. Pain occur as increased the pressure upon and injury to nerve ending.

  1. Loss of Function (FunctioLaesa) :

This is due to partly to mechanical swelling and partly to distribution of tissue.

Tissue Changes in the Inflammatory Process:

1.Circulatory Changes

(a).Momentary Conditions:.

                                                Immediately upon application of the irritant to the issue, the blood vessels are constricted. This is very short.

(b). Dilation:

                        The momentary conditions of the vessels is quickly followed by their direction. Which occurs in arteriolesand vennules, and not capillaries.

Process of “Inflammation”:

Stimulus Recognition:

1.Stimulus is recognized by the inflammatory cells . process i- e Macrophages, Histocytes. Mastocytes (PRRs) “Pattern recognizing Receptors’.

  1. The eclls have (PRRs) Pattern recognition receptors, these receptor recognize. Pathogens.
  2. Release of inflammatory mediators that shows all the signs of inflammation.

Changes in blood vessels:

Momentory Conditions:

                                    As stimulus apply the blood vessels constrict.

(a).Blood flow:

As the endothelial cells lining swell now the blood flow diminished.

Due to flow of passage of plasma out of blood cause blood  viscosity.

Now “Leukocytes” move towards endothelial Linning and make it rough and

“Margination”the leukocytes or no attract by “salectians are adhesion male cedes that ad here with integrinsmalecvles of Navtrqonils.


            It now reduce the blood flow and stasis occur.

Changes in Blood Secretions:

The normal blood  consist on two zone.

  1. Axial stream:

 Cellular Components.

  1. External Stream:

As the permeability of vessel leaked out as fan  inflammatory Exudate.

Emigration of leukocytes: Extravasations

The process of moving of leukocytes out side of vessels is Called “ Emigration”

When the nasals is dial ate by grandees mast cells Phage stair

Diapedesis of Erythrocytes: 

Distribution of erythrocytes RBCs toward peripheral and then leakage through the capillaries wall is called “Diapedesis”.

Exudates Function:

Out all cellular and internaladebri and having immune globulins which Phagocytosed. The pathogen, and enzymatic ally digested the cellular debries.

Exudates composition:

Plasma is blood is product g phoyocytosis  form exudates.

This exudates cause swelling g pain .

Servos, RBCs, WBCs break down products, fibrinogen, tissue debris.


Types of inflammation


1.Acute non – Suppurative Inflammation:

Non- Suppurative inflammation is  Characterized by the absence of pus formation .

1.Serous inflammation:

(i) Serous enudafe comprises of lumph and occurs most often in serous cavities such as  joints, tendons , sheath, pericardial sac, plural and peritoneal cavities, ventricles of the brain and meningeal space.

(ii)  It occurs also in skin and mucous membranes in the from of blisters or vesicles

(iii) It is often the first enudate to appear on mucous  surface in catarrhal inflammation.

(iv) the casuse is often a relatively milled irritant.

2.Catarrhal inflammation:

(i).Catarrhal exudates is thin, clear or slightly viscid in consistency produces by milled irritant acting upon mucous membrane .

(ii) it consist of lymph, mucin and descumated epithelial cells and  leukocytes.

(iii) the most prominent element is mucin produce by the stimulatory action of an irritant on the mucous surface. During early stage, catarrhal enudate contains much lymph but later it mined with many leukocytes.

3.Fibrous Inflammation:

(i)Fibrous exudates may occur within tissue, upon mucous and serous surface.

(ii) where it has the appearance of a pale yellow or white membrane.

(iii) when associated with edema it imparts a jelly like consistency and is often  called “ Gelatinous inflammation”

  1. HaemorrhagicFormation:

Haemorrhagic  exudates is the result of injury to blood vessels by severe irritant. Such as bacillus anthraces. Member of pasturella group and some coccidian.

  1. Other Farmation of inflamation

            It the irritant is so severe as to cause out right necrosis of a tissue the condition is called Acute necrotic inflammation.

Chronic or non suppurative  inflammation:


  1. Chronic inflammation proliferative changes are more marked and there are little or no vascular changes.

(ii) the most conspicuous cells of chronic inflammation is the fibroblast.

 Which shows intensive proliferation.

(iii) During the early stage chronic lesions are quite cellular, but as time passes they become less cellular and proliferative changes take the upper hand.

(iv) Finally, the connective tissue cells become mature and the process no long remain inflammation. It is fully healed lesion which become firm and is designated of a pale yellow or white membrane as fibrous indurated, or organized tissue a fibroused  quarter of cow  udder fallowing chronic mastitisis good enample of this type .

  1. the digestive changes in specialized cells of the parenchymatous organs are also followed by proliferative change and fthe dead tissue is replaced by fibrous tissue
  2. the area become firm and its function is impaired. it usually shrink as chronic nephritis and cirrhosis of liver.
  3. It Chronic inflammation offected tissue never completely refurn to the hormal state . rom the stand point of health of is less dangerous to have a slowly developing chronic inflammation of a vital organ then rapidly destructive acute form .
  4. How ever the end result of chronic form is also serious because of induration and fimpaired function . the organ either fail to perform function completely or the condition may be affected other closely related organs and cause death.

Acute and fchronicsuppurative inflammation



(i) A large number of micro organisms are associated with pus formation.i.e they are capable of causing suppurative inflammation among them are staphylococci,Escherichia coli, corynaebacteriumpyogenes, Actinobaccillyusequnli, actinomycesbovis, and action bacillus lignieresi\

(ii) Beside pus formation organisms, some inorganic and forganic chemicals such as mercuric chloride, turpentine and croton oil, exert as similar influence.

(iii) Acute suppurative inflammation being in the same way as the same way as the non-suppurative inflammation .the principal difference of being that the predominant cells in the enuclate are neutrophils which are called microphages

(iv) The neutrophil which die during the inflammatory process liberate certain proteolysis enzyme from Lysosomes. Diget the dead tissue and fconvert it to semifluid, creamy mass called Abscess.

5. Chronic Suppurative inflammation confined to the rle in that the vascular change become less prominent and proliferative changes predominate.

Ordinarily that exudative changes are nto so prominent encept in a few cases such chronic suppurative rhinitis and chronic suppurativemeteritis.


Granulamatous Inflammation.


(i) Although most of these cases of inflammation are of non. Suppurative or suppurative nature the granulamatous type is associated with certain specific infectious diseases transmissible to man and animals. These discases are caused by micro organisms which are either than bacteria, yeast, mould , fungi or protozoa produce chronic granulamatons reaction.

(ii) it granulamatous lesion the vascular changes ae at the minimum where as exudates changes are characterized by a small amount to fluid and excessive accumulation of inflamatexy cells. Particularly the large mononuclear leukocytes.

(iii) there is tendency for nodules formation at the site of local inflammatory reaction due to entensive proliferation of tissue macrophage or histiocytes.

The cellular reaction in chronic granulomatious inflammation this comprises of encessive proliferation of large mononuclear leucoytes.

Resolution. When blood nesses comes to the nomalayer the inflammation called nasality.

On the  basis of duration:

  • Preacute for shart time

O – 4 hours (A.I )

  • Acute 9 – 6 hours , swelling pain etc is few days.
  • Sub – acute it is for day or when a good.
  • Chronic it is for months and due to virus, bacteria runs up to years.



Fever is the abnormal elevation of body temperature is one of the most prominent systemic manifestations. especially when the inflammation is

associated with infection.


Fever is a syndrome in which there is beside rise of body temperature (pyrexia). A disturbance in metabolism and various   functional distmbances such as increased in pulse rate. Anorexia nausea. Vomiting constipation increased these scanty urine and dehydrating.

Pathogen sis of fever:

Recently new facts have come to light regarding the production of fever its is new established that the venous factors mimed above do not withes produced Fever Direly hut that they act entirely by releasing endogens progens (Eps ) From the leucocytes.

It is know thought that cytokines. Mainly interleukin –I (ii-i)and tumor neurosis factor(TNE) are Involved in the origin of the fever . these cytokines are produce by leukocytes and perhaps also by the other cells in response to infections agents. Or to Immunology and toxic reactions and reactions and release to circulation. They reach the brain and interact with Vascular receptors in the thermoregulatory centre of the Hypothalamus. Either by direct action of the cytokines  or more likely. Through local prostaglandin (PGE ) )Production. Information is transmitted from Hypothalamus. To the vasomotor cent. This result in sympathetic never stimulation. Vasoconstriction of the skin  vessels. Decease in heart dissipation and fever

Causes of fever:

Among the most common causes of fever are bacteria,

  • Endotoxins of gram negative bacteria: these are bacteria pyrogens they formed part if the cell wall of gram-negative bacteria.
  • Gram positive bacteria : the fever producing activity of gram positive bacteria are ;markedly different the former being more potent as fever producer
  • Viruses: the phylogenic factor is closely associated with the viral particle. However, little is know at the present bout the specific factors in viruses that  Cause faver.
  • Examples being trypanosomes. piroplasma and an plasma.
  • Fungi and rickettsiac
  • Hypersensitivity: the essential mechanism appears to the formation. of antigen- antibody complexes which are the initial stimulus for pyrogen release.
  • Mechanical injuries: such as sever crushing. Extensive surgical operations.
  • Vascular disorder producing infarcts, such s myocardial infarction.
  • Neoplasm: most of the malignity tours may cause fever due to their undergoing degenerative and necrotize changes.

Changing in fever

CIRCULATION: increased pulse rate. Lowered blood pressure

RESPIRATION: increased respiration. This may be brought about by the action of CO2 on the respiratory rate. Due to increased metabolism of fever more Co2  produced.

The Course f the fever

  1. The cold stage or period of rising temperature this is also the initeastage of shivering. During this period the temperature is risks but the preselect

Cold and region occur due to contraction of cancerous blood vessels.

  1. The hot stage is the period of sustained high temperature. The fastigium or flush. Her: the temperature reaches to the maximum. The erson feel hot as the corneous vessels are dilated.
  2. The sweating phase: is the period of falling temperature or defervescence the temperature being to fall slowly by lyses and the patient swears profusely.

Function of fever

These are beneficial and include:

  1. Increased Plagocytosis, moderate rise in temperature merited the activity of neutrophils
  2. Increased production of neutrophils.
  3. Distribution of the leucocytes is accletated due to increased velocity of blood.
  4. Formation of antibodies more quickly and in large quintiles.
  5. Bacteria cannot thrive at higher temperature And so to a certain extent fever is bacte
  6. Antigen antibody reaction occurs more rapidly.

Reference books:


  • Veterinary pathology of GantiShastry
  • Veterinary general pathology of DR Irfan
  • Veterinary general pathology of Dr J.L regard


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Notes of Pathology