Preface

Agam is a group of budding medicos, who are currently doing their under graduation in
various Medical Colleges across Tamil Nadu and Pondicherry. The group was initiated on 18th
November 2017, in the vision of uniting medicos for various social and professional causes.

We feel delighted to present you Agam Pathology notes prepared by Agam Divide and Rule
2020 Team to guide our fellow medicos to prepare for university examinations.

This is a reference work of 2017 batch medical students from various colleges. The team
took effort to refer many books and make them into simple notes. We are not the authors of the
following work. The images used in the documents are not copyrighted by us and is obtained from
various sources.

Dear readers, we request you to use this material as a reference note, or revision note, or
recall notes. Please do not learn the topics for the 1st time from this material, as this contain just the
required points, for revision.
Acknowledgement

On behalf of the team, Agam would like to thank all the doctors who taught us Pathology.
Agam would like to whole heartedly appreciate and thank everyone who contributed towards the
making of this material. A special thanks to Vignesh M, who took the responsibility of leading the
team. The following are the name list of the team who worked together, to bring out the material in
good form.

• Neelavathi S
• Vignesh. J
• Dharani D
• Gokula Samyuktha S
• Mahalakshmi K
• Dhyaneshwar Ra
• Harish Kumar M
• Hariharan V P
• Hannasha M Priyadharshini
• Sowmya T D
• Vimal K
• Vignesh. M
• Varsha L
• Muthamil Selvi E
• Kaushik N R
 DISEASES OF IMMUNE SYSTEM
ESSAY:
1. Classify amyloidosis. Details about it
2. SLE
3. Morphology of Graft Rejection
4. AIDS
5. Hypersensitivity reactions
6. Classify primary immunodeficiency syndromes. Details about it

SHORT NOTES:
1. Graft versus Host Disease
2. Major Histocompatibility Complex
3. Mast cell
4. T- Lymphocytes
5. Primary amyloidosis
6. Bence-Jones proteins
7. Mechanisms of autoimmunity
8. Fibronectin
9. Acute Phase reactants
10.Hyper IgM syndrome

SHORT ANSWERS:
1. Sites of biopsy of amyloidosis
2. Staining character of amyloidosis
3. Sago spleen
4. Chronic granulomatous disease
5. Morphology of spleen in SLE
6. Amyloid reaction
7. LE phenomenon
8. NK cells
9. Anti-nuclear antibodies
10.Cytokines

UPDATES

PATHOLOGY AGAM
ESSAY
1. AMYLOIDOSIS
 It is a condition associated with a number of inherited and inflammatory disorders in
which extracellular deposits of fibrillar proteins are responsible for tissue damage and
functional compromise
 Physical nature:
 Non-branching fibrils (Electron microscopy)
 Cross –beta pleated sheets (X-ray crystallography) {reason for apple green
birefringence in PPL}
 Chemical nature: 95%- Fibrillar protein, 5%- P component
 Three most common forms of amyloid are:
 AL (Amyloid light chain)
 AA (Amyloid associated)
 Aβ (β-Amyloid protein)
 Other forms of amyloids:
 ATTR (Transthyretin)
 Aβ2m (β2-Microglobulin)
 Prion proteins

CLASSIFICATION OF AMYLOIDOSIS:

Amyloidosis

Systemic Hereditary Localized

SYSTEMIC/GENERALIZED AMYLOIDOSIS
 Primary Amyloidosis:
 Primary amyloidosis is associated with Plasma Cell Dyscrasias
 Normally plasma cells secrete Immunoglobulins.
 In plasma cell dyscrasias, there is abnormal increase in secretion of light chains of
Ig which forms amyloid
 5-15% of Multiple myeloma patients develop systemic amyloidosis
 Secondary Amyloidosis:
 It is also known as reactive systemic amyloidosis
 It is known as secondary amyloidosis because it is secondary to an associated
chronic inflammatory condition (Rheumatic arthritis/Tuberculosis/Crohn disease/
ulcerative colitis) or cancers (Hodgkin lymphoma/Renal cell carcinoma)
 Here, SAA synthesis by liver cells is stimulated by IL-6 and IL-1
AGAM PATHOLOGY
  Hemodialysis-associated amyloidosis:
 Patients of renal failure undergoing long-term dialysis can develop amyloidosis as
a result of increased β2-Microglobulin
 These patients present with carpal tunnel syndrome due to β2-Microglobulin
deposition.

HEREDITARY AMYLOIDOSIS:
 Familial Mediterranean fever:
 This is an Autosomal recessive autoinmflamatory syndrome with
 Here there is an excessive production of IL-1 in responsive to inflammatory
response.
 Familial Amyloidotic Polyneuropathy:
 This is an autosomal dominant disorder.
 Here ATTP (transthyritin) is accumulated as amyloid

LOCALIZED AMYLOIDOSIS:
 Senile cardiac amyloidosis (ATTR):
 Senile cardiac amyloidosis is seen in 50% of people above the age of 70 years.
 The deposits are seen in the heart and aorta.
 The type of amyloid in these cases is ATTR but without any change in the protein
structure of TTR.
 Senile cerebral amyloidosis (Aβ, APrP):
 Senile cerebral amyloidosis is heterogeneous group of amyloid deposition of
varying etiologies that includes sporadic, familial, hereditary and infectious.
 Some of the important diseases associated with cerebral amyloidosis and the
corresponding amyloid proteins are:
 Alzheimer’s disease (Aβ),
 Down’s syndrome (Aβ) and
 Transmissible spongiform encephalopathies (APrP) such as in:
 Creutzfeldt-Jakob disease
 Fatal familial insomnia
 Mad cow disease.
 In Alzheimer’s disease, deposit of amyloid is seen as
 Congophilic angiopathy (amyloid material in the walls of cerebral blood
vessels),
 Neurofibrillary tangles and
 In senile plaques.

PATHOLOGY AGAM
  Endocrine amyloidosis (Hormone precursors):
 Some endocrine lesions are associated with microscopic deposits of amyloid. The
examples are as follows:
 Medullary carcinoma of the thyroid (from procalcitonin i.e. ACal).
 Islet cell tumour of the pancreas (from islet amyloid polypeptide i.e. AIAPP or
amylin).
 Type 2 diabetes mellitus (from pro-insulin, i.e. AIns).
 Pituitary amyloid (from prolactin i.e. APro).
 Isolated atrial amyloid deposits (from atrial natriuretic factor i.e. AANF).
 Familial corneal amyloidosis (from lactoferrin i.e. ALac).

 Localised tumour forming amyloid (AL):

 Sometimes, isolated tumour like formation of amyloid deposits are seen e.g. in
lungs, larynx, skin, urinary bladder, tongue, eye, isolated atrial amyloid.
 In most of these cases, the amyloid type is AL.

MORPHOLOGY:
KIDNEY:
 Amyloidosis is most common in kidney.
 Amyloid deposition begins from mesangium and involves other parts later.
 Patient presents with:
 Proteinuria,
 Urinary casts are positive
 Kidney size is increased

SPLEEN:
 Sago spleen - Deposits limited to splenic follicles, producing tapioca like appearance
on gross (Like javvarisi / Sabudhana)
 Lardaceous spleen – Amyloid involves walls of splenic sinuses and connective tissue
framework in red pulp (World Map Like gross Picture)

LIVER:
 Hepatomegaly
 Amyloid appears 1st in the space of disse and progressively encroaches adjacent
parenchyma

HEART:
 More commonly involved in senile systemic amyloidosis.
 Deposits begin in sub-endocardium affect the conduction system causing arrhythmia.
 Restrictive cardiomyopathy(most common cause is amyloidosis)

AGAM PATHOLOGY
JOINTS:
 Knee joint and wrist joint are most commonly involved.
 In wrist it causes carpal tunnel syndrome

SKIN: Pinch purpura is seen due to involvement of perivascular area

GIT: Macroglossia

DIAGNOSIS:
Specimen is obtained from abdominal fat pad aspirate > rectal biopsy >tongue biopsy.
 Staining (Congo red staining)
 Under polarized light Apple green birefringence
 Under light microscopy – salmon pink appearance
 Electron microscopy – Non branching fibrils are observed
 X-Ray crystallography – reveals β-plated sheets
 Scintigraphy – done with the help of amyloid P
 Gross stain:
 On painting the cut surface of kidney gross specimen with lugols iodine, it
changes to mahagony brown color.
 Then on addition of H2SO4 it turns to blue color in case of amyloidosis
 Other stains used for amyloid:
 H&E stain ,
 PAS (Magenta colored),
 Methyl violet and crystal violet,
 Trioflavin stain (immunofluroscenece stain)

DISEASE/CONDITION AMYLOID DEPOSITED

1o Amyloidosis AL TYPE
(Eg: Plasma cell dyscrasias)
2o Amyloidosis AA TYPE
(Chronic inflammation/cancers)
Hemodialysis associated dialysis Aβ2 TYPE
Alzheimer disease Aβ TYPE
Senile amyloidosis ATTR (NORMAL FORM) TYPE
Familial polyneuropathy ATTR (MUTATED FORM) TYPE
Familial medetirrenean fever AA TYPE
Prion disease APrP TYPE
Diabetes mellitus (more common in type 1) AIPPA TYPE (OR AMYLIN)
Medullary thyroid cancer ACal type

PATHOLOGY AGAM
2. SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic lupus erythemaosus (SLE) is an autoimmune disease involving multiple
organs, characterized by a vast array of auto antibodies, particularly antinuclear
antibodies (ANAs), in which injury is caused mainly deposition of immune complexes and
binding of antibodies to various cells and tissues.

TYPES:
 Systemic or disseminated form is characterized by acute and chronic inflammatory
lesions widely scattered in the body and there is presence of various nuclear and
cytoplasmic auto antibodies in the plasma.
 Discoid form is characterized by chronic and localised skin lesions involving the bridge
of nose and adjacent cheeks without any systemic manifestations. Rarely, discoid
form may develop into disseminated form.

SPECTRUM OF AUTOANTIBODIES IN SLE:

The hallmark of SLE is production of autoantibodies. Apart from their value in
diagnosis and management of patients with SLE, these autoantibodies are of major
pathogenic significance.
Autoantibodies produced in SLE are as below:
 Anti Nuclear antibodies(ANAs): These are directed against nuclear antigens and are
grouped as:
 Antibodies to DNA
 Antibodies to histones
 Antibodies to non-histone proteins
 Antibodies to nucleolar antigens
 Antiphosholipid antibodies are present in about 30% of SLE patients
 Antibodies to dsDNA and Smith(S) antigen are also diagnostic of SLE

STAINING PATTERNS:
 Diffuse staining – seen in all types of autoantibodies
 Rim staining – seen in antibodies against ds-DNA
 Speckled pattern – seen most commonly
 Nucleolar pattern – seen in antibodies against RNA
 Centrometric pattern – seen in patients with SLE and systemic sclerosis

ETIOPATHOGENSIS:
The fundamental defect in SLE is the failure of mechanisms that maintain self-tolerance.
GENETIC FACTORS:
 Family members have a high risk for developing SLE
 There is a high rate concordance in monozygotic twins
 Alleles of HLA-DQ locus have been linked to produce certain autoantibodies

AGAM PATHOLOGY
IMMUNOLOGIC FACTORS:
 Several immunologic aberrations may result in persistence and uncontrolled
activation of self-reactive lymphocytes.
 Failure of self-tolerance in B cells
 CD4+ helper T cell may escape tolerance and produce pathogenic autoantibodies to
nuclear antigens
 TLR engagement by nuclear DNA and RNA contained in immune complexes may
activate B lymphocytes
 Type I Interferons play a role in lymphocyte activation of B cells

MECHANISM OF INJURY:
 Type III hypersensitivity reaction:
 Most of the systemic lupus is caused by immune complexes DNA- anti- DNA
complexes can be detected in the glomeruli and small blood vessels.
 T cell infiltrates are also frequently seen in kidneys.
 Type II hypersensitivity reaction:
 Autoantibodies specific for red cells, white cells and platelets opsonize these cells
and promote their phagocytosis and lysis
 Antiphospholipid antibody syndrome(APLA):
 Patients with antiphospholipid antibodies may develop venous and arterial
thromboses.
 When it is
 Associated with SLE → 2o antiphosholipid antibody syndrome
 Not associated with SLE → 1o antiphospholipid antibody syndrome

CLINICAL FEATURES:
 SLE, like most other auto immune diseases, is more common in women in their 2nd to
3rd decades of life.
 SLE is a multisystem disease and thus a wide variety of clinical features may be
present.
 The severity of disease varies from mild to intermittent to severe and fulminant.
 Usually targeted organs are musculoskeletal system, skin, kidneys, nervous system,
lungs, heart and blood vessels, GI system and haematopoietic system.
 Fatigue and myalgia are present in most cases throughout the course of disease.
 Severe form of illness occurs with fever, weight loss, anemia and organ related
manifestations.
 The disease usually runs a long course of flare-ups and remissions
 Renal failure is the most frequent cause of death.

PATHOLOGY AGAM
MORPHOLOGY:
KIDNEY:
Upto 50% of SLE patients have significant renal involvement. Six patterns of
glomerular disease are seen in SLE:
 Class I: Minimal mesangial lupus nephritis
 Very uncommon and characterized by immune complex deposition in mesangium
 Class II: Mesangial proliferative lupus nephritis
 Characterized by proliferation of mesangial cells as well as immune complex
deposition on mesangium
 Class III: Focal lupus nephritis
 There is involvement of <50% of glomeruli.
 Affected glomeruli may exhibit swelling and proliferation of endothelial and
mesangial cells associated with leukocyte accumulation, capillary necrosis and
hyaline thrombi.
 Patients presents with mild hematuria, proteinuria and may progress to Acute renal
insuffiency
 Class IV: Diffuse lupus erythamatosis
 Most common and severe form of lupus nephritis.
 There is involvement of >50% glomeruli and show proliferation of mesangial,
endothelial and epithelial cells.
 Lesions may progress to scarring of glomeruli.
 Patients present with hematuria, proteinuria and mild hypertension. (Wire loop
lesion)
 Class V: Membranous lupus nephritis
 Due to sub epithelial deposition of immune complexes, there is diffuse thickening of
capillary walls. It is associated with proteinuria or nephrotic syndrome.
 Class VI: Advanced sclerosing lupus nephritis
 It is characterized by sclerosis of >90% of the glomeruli and represents end stage
renal disease.

SKIN:
 Butterfly rash – erythema in face along bridge of nose and cheeks (MALAR RASH)
 Utricaria, bullae, maculopapular lesions
 Vasculitis with fibrotic necrosis

CVS:
 Myocarditis
 Mitral / Aortic valve stenosis or regurgitation
 Libman – Sachs endocarditis
 Coronary artherosclerosis

AGAM PATHOLOGY
Blood vessels: Acute nerotizing vasculitis of small arteries and arterioles and may progress
into fibrosis and lumen narrowing
Spleen: Spleenomegaly, capsular thickening and follicular hyperplasia
Lungs: Pleuritis, plueral effusion, interstital fibrosis and so pulmonary hypertenti
Joints: Non erosive synovitis
CNS: Neuropschycotic syndromes ascribes to vasculitis or non-immune occlusion of small
vessels

3. MORPHOLOGY OF GRAFT REJECTION (Renal Graft)

HYPERACUTE REJECTION:
 Occurs within minutes / hours after transplantation
 Gross
 Cyanotic, mottled, flaccid
 Few drops of bloody urine may be excreted
 Cortex undergoes infarction / necrosis
 Kidney becomes non-functional
 Microscopy
 Endothelial injury
 Neutrophils accumulation
 Fibrin-platelet thrombi
 Fibrinoid necrosis of vessel wall

ACUTE REJECTION:
 Occurs within days/after termination of immunosuppressive therapy.
 Acute cellular/T-Cell mediated rejection
 Type-I : Tubulitis
 Type-II : Endotheliitis
 Type-III : Necrosis of vessel wall
 Shows cellular infiltration of CD4+ & CD8+ & T-Cells
 Acute Ab- mediated rejection
 Damage to glomeruli & blood vessels
 Deposition of C4d

PATHOLOGY AGAM
CHRONIC REJECTION:
 Intimal thickening with inflammation.
 Glomerulopathy
 Peritubular capilaritis
 Shows interstitial mononuclear cell infiltrates, including NK cells & plasma cells

FACTORS INFLUENCING GRAFT REJECTION

 HLA matching between donor and recipient
 Strong immune response for allografts
 T-Cells play a critical role
 Direct killing of graft cells by CD8+ cytotoxic T-Cells
 CD4+ Tcells  cytokine release  inflammatory reaction
 T-Cells contribute to both acute and chronic rejection
 Role of Antibodies:
 Preformed antibodies in recipient who had previously undergone transplantation /
blood transfusion  Hyperacute rejection
 Anti-donor antibodies formed after transplantation  acute / chronic rejection
 Immunosuppressive therapy:
 Steroids – reduce inflammation
 Mycophenolate mofetie – inhibit lymphocyte proliferation
 Tacrolimus – inhibit T-Cells
 Pooled iv IgG – suppress inflammation
 Plasmapheresis
 Opportunistic infections  reactivation of polyoma virus causes renal graft
rejection
 Donor’s age, genetic considerations, no. of acute rejection episodes also influence
graft survival.

AGAM PATHOLOGY
4. AIDS
INTRODUCTION:
 AIDS: Acquired Combined Immunodeficiency Syndrome
 Caused by: HIV [ Human Immunodeficiency Virus]
 Characterized by: Severe immunosuppression causing
 Opportunistic infections
 Secondary neoplasms
 CNS manifestations
70% Africa
 People living with AIDS: 34 million
20% Asia
EPIDEMIOLOGY:
High risk groups include:
 Homosexual / bisexual men
 IV drug abusers
 Hemophiliacs
 Heterosexual contacts (mostly from men to women)
 Recipients of blood and its components
 HIV infection of the newborn

MAJOR ROUTES OF TRANSMISSION:

 Sexual transmission (>75%):
 Carried by semen
 Enters recipients ’body through:
 Abrasions in oral or rectal mucosa
 Direct contact with mucosal lining cells
 Viral transmission occurs through:
 Direct inoculation into blood vessel
 Infection of dendritic or CD4+ cells
 HIV transmission is increased with coexisting STDs. Because of the genital
inflammation in such diseases, there is:
 Increased concentration of virus
 More virus containing cells in the fluids

 Parenteral transmission:
 IV drug abusers
 Hemophiliacs (Factor VIII and IX)
 Frequent blood transfusion recipients

 Mother to child transmission:

 Transplacental: Through placenta, Intrapartum: At birth (birth canal). Peripartum:
Breast milk

PATHOLOGY AGAM
ETIOLOGY – HIV:
 Non transforming human retrovirus
 Family: Lentivirus
 2 forms:
 HIV-1: US, Europe and most of the world
 HIV-2: West Africa and India

STRUCTURE OF HIV:
 Spherical in shape
 Outer envelope (derived from host cell membrane)
 Inner core, containing:
 Capsid protein – p24
 Nucleocapsid protein – p7/p9
 Enzymes
 Reverse transcriptase: Form proviral DNA
 Integrase
 Protease: Cleave precursor proteins
 Genome: HIV-1 RNA with gag, pol, and env genes
 p24 is the most abundant viral antigen [detected by ELISA]
 The viral core is surrounded by matrix protein – p17
 Envelope contains 2 glycoproteins gp120 and gp41

Gp 120 binds to Conformational gp120, CD4 binds to

CD4 receptor change chemokine receptor
(particularly CCR5

Attack Gp 41 expose "Fusion

new cell peptide” (hydrophobic)

LIFE CYCLE OF HIV

Budding of Membrane
mature virion fusion

Synthesis of Integration of provirus

Assembly
HIV proteins with host genome

AGAM PATHOLOGY
VIRAL REPLICATION:
 HIV is inefficient at infecting naïve T-cells
 Presence of the enzyme APOBEC3G
 Cytosine to Uracil mutation in viral protein
 In mature T-cells: APOBEC3G is inactivated
 Viral protein Vif: promotes degradation of APOBEC3G
 Subversion from within
 Sequences flanking HIV contain NF-ҡB binding site
 Stimulation of cells (by antigen or cytokine) causes the release of NF-ҡB (which
enters the nucleus and binds to the promotor of several genes, including those of
cytokines)
 This, in turn, activates transcription of HIV proviral DNA

MECHANISM OF T-CELL DEPLETION:

 Increased membrane permeability (due to budding of virions)
 Interference of protein synthesis (due to viral replication)
 Activation induced cell death
 Pyroptosis
 Loss of precursors of CD4+ T-cells
 Syncytia of infected and uninfected cells (Fused cells die within hours)
 Qualitative defects – Observed in asymptomatic HIV patients

Infection of non T-cell

Dendritic cell Macrophage

vpr gene
Mucosal DC Follicular DC

Trap virus in germinal Transport to regional

centers of lymph nodes lymph nodes and
with anti-HIV antibodies infect CD4+ T cells

PATHOLOGY AGAM
PHASES OF HIV:
Acute retroviral syndrome:
 Infection of CD4+ T cells and Dendritic cells in the mucosa
 Regional lymph nodes infection (as shown in flow chart) – within days
 Viremia. Dissemination of virus – 3 to 7 weeks
 Development of immune response
 N.B.:
 Occurs – 3 to 6 weeks after exposure
 Resolves – in 2 to 4 weeks (spontaneously)
 HIV-1 RNA levels (measure of extent of viremia) is a marker of HIV progression
 Viral set point – the viral load at the end of acute phase (equilibrium b/w virus
and response are attained)
 CDC classified HIV into 3 categories based on the CD4+ count:
 ≥500
 200 – 499
 <200

Chronic infection – Phase of clinical latency:

 Lymph node and spleen – primary sites for proliferation of virus
 Circulating T cells do not harbor virus
 Continuous destruction of CD4+ T cells in lymphoid tissues
 Hence, there is steady decline in CD4+ T cell count
 Virus may switch class from relying solely on CCR5, CXCR4 or both
 Possible opportunistic infections:
 Oral and vaginal candidiasis
 Herpes zoster
 M. tuberculosis
 Autoimmune thrombocytopenia

Clinical AIDS:
 Breakdown of host defense and severe increase in plasma virus
 Typical symptoms:
 Long term fever (>1 month)
 Diarrhea
 Fatigue
 Weight loss
 Onset of AIDS indicator diseases (given below)

AGAM PATHOLOGY
CLINICAL FEATURES OF AIDS:
Opportunistic infections:
 Protozoan:
 Cryptosporidiosis/ isosporidiosis – Persistent diarrhea
 Pneumocytosis (P. jiroveci) - Pneumonia
 Toxoplasmosis - Encephalitis
 Fungal:
 Candidiasis – Oral, vaginal and esophageal
 Cryptococcosis - Meningitis
 Coccidioidomycosis
 Histoplasmosis
 Bacterial:
 Mycobacteriosis (M. avium-intracellulare, M. tuberculosis)
 Narcoidosis
 Salmonella
 Viral:
 Cytomegalovirus – Eye and GIT
 Herpes simplex virus – Mucocutaneous ulceration
 Varicella zoster virus
Neoplasms:
 Kaposi sarcoma:
 Vascular tumor
 Proliferation of spindle-shaped cells
 Express markers of endothelium and smooth muscle
 Produce proinflammatory and angiogenic factors
 Slit-like vascular spaces (lesion- primitive mesenchyme)
 Caused by KS herpesvirus (KSHV) / human herpesvirus 8 (HHV8)
 Linked with primary effusion lymphoma and Castleman disease
 Lymphomas:
 Proliferation of B cells with chronic, latent viral infection
 B cell hyperplasia in early HIV infection
 Increased risk of mutation
 MYC – Burkitt lymphoma
 BLC6 – Large B cell lymphoma
 Hodgkin’s lymphoma
 Oral hairy cell leukoplakia
 Carcinoma of cervix and anal cancer
PATHOLOGY AGAM
CNS manifestations:
 Meningoencephalitis
 Aseptic meningitis
 Vacuolar myelopathy
 Peripheral neuropathy
 HIV associated neurocognitive disorder

TREATMENT:
HAART:
 Highly Active Anti-Retroviral Therapy
 a.k.a Combined antiretroviral therapy
 Combination of 3 or 4 drugs inhibiting HIV infection at many steps
 Side effects:
 Lipoatrophy (loss of facial fat)
 Lipoaccumulation
 Insulin resistance
 Peripheral neuropathy
 Primary cardiovascular, renal and liver disease
Immune reconstitution inflammatory syndrome:
 Patients with advanced disease, when given antiretroviral therapy, develop
paradoxical clinical deterioration.
 No vaccine is currently available
 Hence, Prevention, Public health measures and ART are key measures.

MORPHOLOGY:
 Lesions in the brain
 B cell hyperplasia with enlarged follicles (early stage)
 Lymphoid involution (late stage)
 Germinal centers – Hyalinized
 “burnt out” lymph nodes (atrophic)
 Spleen and thymus “ –waste-lands” (absence of lymphocytes)

AGAM PATHOLOGY
5. HYPERSENSITIVITY REACTION
Hypersensitivity is an excessive and immune response to antigen leading to tissue
injury, disease or sometimes death in a sensitized individual.
TYPES:
 Immediate / Type1
 Ab-mediated / Type2
 Immune complex mediated / Type3
 Cell mediated/Type4

IMMEDIATE / TYPE1 HYPERSENSITIVITY:

It is a rapid immunologic reaction occurring in a previously sensitized individual that
is triggered by binding of antigen to Ig E antibody on surface of mast cell.

PATHOGENESIS:
First exposure

Exposure to an allergen (Ag)

Ag taken up by APC into circulation

Differentiated T cells and TH2 cells

IL-5, IL-6 IL-4, IL-13

Recruitment of Eosinophils ↑ IgE production

Sensitizition and actions of mast cell:

 Mast cell have high affinity FceRI receptors which is specific for Fc portion of IgE
 During first exposure mast cell is coated with IgE and is called sensitized mast cell

PATHOLOGY AGAM
On subsequent exposure

Ag-Ab Reaction on surface of mast cell

Degranulation and activation of mast cell

Early phase reaction Late phase reaction

Due to preformed mediators (histamine) Due to LT’S, Cytokines, Chemokines

 Vasodilation  Leukocyte infiltration

 Vascular leakage  Epithelial damage
 Smooth muscle spasm  Bronchospasm

EXAMPLES
 Asthma
 Hay fever
 Allergic rhinitis
 Allergic dermatitis
 Pollen allergy

TESTS
 Casoni test
 Theobald smith test
 PK reaction
 Schultz dal Phenomenon

ATOPY
 Genetic predisposition to type 1 hypersensitivity
 Atopic individuals tend to have high serum IgE levels and more IL4 producing TH cells
than does general population.
 Exposure to drugs – antibiotic like penicillin can precipitate anaphylactic shock
 Insect bite

AGAM PATHOLOGY
TYPE 2 / ANTIBODY MEDIATED
Antibody that react with Antigens present on cell surface or extracellular matrix
cause disease by destroying these cells, triggering inflammation or by interfering normal
function.

PATHOGENESIS:
 Ab are directed against fixed Ag
 Ab can be directed against:
 Cell surface
 Extracellular matrix or Basement membrane

Ag fixed to BM

Ag + Ab on BM activation

Complement activation

C3a, C5a mediated Neutrophil recruitment

Enzyme release

Destruction of Basement membrane

Ag fixed on cell membrane

Destruction of target cells Dysregulation of function of target cells

(a.k.a. type 5 HS rxn)

Opsonisation Complement Fixation

Eg:
 Graves Disease
 Myasthenia gravis

PATHOLOGY AGAM
EXAMPLES: My blood group is Rh positive
 My- Myasthenia gravis
 Blood- Blood transfusion reaction
 Group- Good pasture syndrome
 Is- Insulin resistant diabetes, Immune hemolytic anemia
 R- Rheumatic fever
 H- Hyperthyroidism (Graves disease), Hyperacute rejection
 Positive - pernicious anemia

TYPE 3 / IMMUNE COMPLEX MEDIATED

Ag-Ab complexes produce tissue damage by eliciting inflammation at site of
deposition.
PATHOGENESIS:
 Formation of Immune Complex (IC) (5-7days) Ag + Ab – IC
 Most pathogenic IC: medium sized, formed with slight excess of antigen.
 Deposition of IC: Organs where blood is filtered at high pressure.
 Most common site : kidney , blood , vessels , skin , joints
 IC mediated tissue injury
 IC deposition
 Complement activation
 Tissue destruction
EXAMPLE: SHARP
 S - Serum sickness/SLE
 H - Henloch schloein purpura
 A - Arthus reaction
 R - Reactive arthritis
 P - Post streptococcal glomerulonephritis

ARTHUS REACTION: Localized area of tissues necrosis → due to acute IC vasculitis

Intra cutaneous injection of Ag in Immunized individual

Ag binds with performed Ab and forms IC

Deposition of IC in vessel wall

Superimposed
Fibrinoid necrosis Ischaemic injury thrombosis

AGAM PATHOLOGY
TYPE 4 HYPERSENSTIVITY REACTIONS
PATHOGENESIS:
 Activation of CD4 T cells leads to increased IL-2, IL-12, IFN - gamma leading to
granuloma formation.
 Activation of CD8 T cells leads to direct destruction of viral and tutor cells by FAS-L
mechanism or granzyme perforin mechanism.
EXAMPLES:
 Rheumatoid arthritis
 Multiple sclerosis
 Contact dermatitis
 IBD
 Psoriasis

6. IMMUNODEFICIENCY SYNDROMES
 Immunodeficiencies can be divided into primary or secondary disorders.
 Primary Immunodeficiencies are genetically acquired.
 They are caused due to intrinsic defects in immune system (innate/ adaptive).

Primary Immunodeficiency Syndromes

Defects in Innate Immunity Defects in Adaptive Immunodeficiency a/w

Immunity Systemic Diseases
 Defects in Leukocyte
 Wiskott-Aldrich
function
syndrome
 Deficiencies affecting
 Ataxia Telangiectasia
the complement system

Defects in Lymphocyte Defects in Lymphocyte

Activation and Function maturation
 Hyper IgM syndrome  Severe combined
 Common Variable Immunodeficiency
Immunodeficiency  X-Linked
 Isolated IgA deficiency Agammaglobulinemia
 X-Linked Lympho-  DiGeorge Syndrome
Proliferative syndrome

PATHOLOGY AGAM
DEFECTS IN INNATE IMMUNITY
A. DEFECTS IN LEUCOCYTE FUNCTION:
Leucocyte Adhesion Defect:
 Individuals suffering from Leucocyte Adhesion Deficiency Type -1 have defective
synthesis of β2 Chains shared by LFA-1 and Mac-1 integrins
 Leucocyte Adhesion Deficiency Type -2 – Absence of Sialyl-Lewis X Ligand leading to
defective fucosyl transferase.
 Recurrent bacterial infection due to inadequate granulocyte function.
Defective Phagolysosome Function:
 Chediak-Higashi Syndrome - Autosomal Recessive Condition
 Defective fusion of Phagosomes and lysosomes → defective phagocytic functions.
 Neutropenia, defective degranulation, delayed microbial killing seen.
 Leucocytes have giant granules seen in peripheral smear.
 Albinism, nerve defects, platelet defects seen.
 Gene associated-LYST
Microbicidal Activity Defects:
 Chronic Granulomatous Disease:
 Defective bacterial Killing leading to recurrent infections.
 Disease results from defective gene for phagocyte oxidase which is supposed to
generate superoxide (O2•-) ion.
 Name of disease comes from the macrophage rich inflammation that tries to control
the infection when initial defense is inadequate.
 This leads to collection of activated macrophages in wall of microbes leading to
granulomas.
Defects in TLR signaling:
 TLR3 defect- recurrent HSV encephalitis
 MyD88 defect- destructive bacterial pneumonia

B. DEFECTS AFFECTING THE COMPLEMENT SYSTEM

 C2 deficiency (most common) - Deficiency of C2 or C4 leads to increased bacterial or
viral infections. Alternative pathway is adequate, so no clinical manifestation.
 Alternative pathway component deficiencies are rare.
 C3 is required in both pathways, so deficiency leads to recurrent pyogenic infections.
 Deficiency of C5, 6, 7, 8, 9(membrane active complex) leads to recurrent Neisseria
infections.

AGAM PATHOLOGY
 Deficiency of C1 inhibitor (C1 INH) leads to recurrent hereditary angioedema.
 Proteases are not inhibited which leads to increased kallikrein, releasing vasoactive
bradykinin.
 There is edema of skin and mucosal surfaces (larynx, GIT), leading to asphyxia /
vomiting.

DEFECTS IN ADAPTIVE IMMUNITY

 Defects can be classified based on the component affected, i.e. B-cell or T-cell.
 But the distinctions might not be clear always as T cell defects lead to impaired
antibody formation.
 Therefore these immunodeficiencies can arise from either defect in lymphocyte
maturation or lymphocyte activation.

PATHOLOGY AGAM
DEFECTS IN LYMPHOCYTE MATURATION:
A. SEVERE COMBINED IMMUNODEFICIENCY (SCID):

 SCID is a collection of genetically distinct syndromes which have defects in both

humoral and cell mediated immune responses.
 Oral thrush, diaper rash, failure to thrive seen in infants.

 X-Linked SCID: (50-60%)

 More common in boys.
 Mutation in γ-chain subunit of cytokine receptors.
 IL-7 is required for maturation of T-cell precursors.
 Due to defective IL-7 receptor signaling, defective T-cell development is seen.
 T-cell numbers are reduced with normal B-cell numbers.
 Therefore Ab synthesis is reduced.
 IL-15 receptor is affected leading to lack of maturation and proliferation of NK cells.
 Features:
 Thymus consists of undifferentiated epithelial cells.
 Other lymphoid tissues are hypoplastic.

 Autosomal recessive SCID:

 Deficiency of Adenosine DeAminase (ADA) enzyme.
 Leads to accumulation of deoxyadenosine and derivatives (eg. Deoxy-ATP) which is
toxic to immature T-lymphocytes.
 T-cell numbers are reduced than B-cell.
 Thymus is small and devoid of lymphoid cells.

 Treatment:
 HSC Transplantation is the mainstay of treatment.
 Gene therapy has been successful for X-linked SCID.
 Patients with ADA deficiency have also been treated with HSC transplantation and
introducing the normal ADA gene into T-cell precursors.

AGAM PATHOLOGY
B. X-LINKED AGAMMAGLOBULINEMIA (BRUTON’S AGAMMA GLOBULINEMIA):
 Etiology:
 Mutation in Bruton Tyrosine Kinase (Btk) gene(Xq21.22) which is a cytoplasmic
tyrosine kinase gene.
 Btk gene gives a kinase which is required for maturation of pre B-cell into B-cell
stage.
 Mutation of Btk gene  No B-cell Maturation (blocked at pre B-cell stage)  No
light chains  reduced production of Ig.
 Clinical manifestation:
 Seen in Males and doesn’t manifest till 6 months of age(protective effect of
maternal antibodies)
 Recurrent bacterial infections of respiratory tract like pharyngitis, sinusitis, otitis
media etc.
 Viral infections (e.g. echovirus, polio virus) and Giardia lamblia infections occur.
 Characteristic Findings:
 Absent or markedly decreased B lymphocytes in circulation.
 Decreased serum levels of all classes of Ig’s.
 Underdeveloped of germinal centers in lymph nodes, Peyer’s patches, appendix,
tonsils.
 Absence of plasma cells. Normal T-cell immunity.
C. DIGEORGE SYNDROME (THYMIC HYPOPLASIA):
 Cell mediated immunity due to reduced number of T-cells.
 Etiology:
 DiGeorge Syndrome is a T-cell deficiency arising from failure of development of 3rd
and 4th pharyngeal pouches – which normally gives rise to the thymus, parathyroid
glands, some of the clear cells of thyroid, ultimo branchial body.
 Patients develop:
 C - Cleft lip and cleft palate
 A - Abnormal facies
 T - Thymic hypoplasia
 C - Cardiac defects
 H - Hypocalcemia
 Point deletion (22q11 deletion) in long arm of Chr. 22 seen.
 Clinical manifestations:
 Presents in infancy with congenital heart defects and severe hypocalcemia (due to
hypoparathyroidism)
 Infant prone to recurrent or chronic viral, bacterial, fungal and protozoal infections.
T-cell zones of lymphoid organs are depleted.
PATHOLOGY AGAM
DEFECTS IN LYMPHOCYTE ACTIVATION AND FUNCTION:
A. HYPER-IGM SYNDROME:
 Affected patients make IgM antibodies but are deficient in their ability to produce IgG,
IgA, IgE antibodies.
 For functioning of CD4+ helper T cells, engagement of CD40 by CD40L is required, on
the B cells, macrophages and dendritic cells.
 This causes class switching of Ig’s and maturation of B cells.
 Etiology:
 X-linked form: Caused by mutations in the gene encoding CD40L located on Xq26.
 Autosomal recessive form: Loss-of-function mutations involving either CD40 or
activation-induced cytidine deaminase (AID), a DNA-editing enzyme required for Ig
class switching and affinity maturation.
 Clinical manifestation and findings:
 Serum of patients have High or normal IgM but no IgA or IgE and low levels of IgG.
Patients present with recurring pyogenic infections due to less opsonizing IgG
antibodies.
 Those with CD40L mutations are susceptible to Pneumocystis jiroveci because of
defective macrophage activation.
 IgM antibodies may react with blood cells and cause autoimmune hemolytic
anemia, thrombocytopenia and neutropenia.

B. COMMON VARIABLE IMMUNODEFICIENCY:

 It is a heterogeneous group of disorders in which the common feature is hypo gamma
globulinemia, generally affecting all the antibody classes but sometimes only IgG.
 Affected individuals have normal or near-normal numbers of B cells in the blood and
lymphoid tissues.
 But they are not able to differentiate into plasma cells.
 Both intrinsic B-cell defects, and abnormalities in helper T cell–mediated B cell
activation may cause the antibody deficiency in this disease.

 Etiology: The abnormality is in:

 BAFF: a receptor for a cytokine that promotes the survival and differentiation of B
cells, or
 ICOS (inducible co-stimulator): A molecule that is similar to CD28 which is involved
in T-cell activation and in interactions between T and B cells.

AGAM PATHOLOGY
 Clinical Manifestation:
 They are caused by antibody deficiency, & they resemble those of X-linked
agammaglobulinemia.
 The patients typically present with recurrent sinopulmonary pyogenic infections.
 In addition, about 20% of patients have recurrent herpesvirus infections.
 Individuals are also prone to the development of persistent diarrhoea caused by G.
lamblia.

C. ISOLATED IGA DEFICIENCY:

 Affected individuals have extremely low levels of both serum and secretory IgA.
 Etiology:
 The defect is impaired differentiation of naive B lymphocytes to IgA-producing
plasma cells.
 The molecular basis is unknown.
 Defects in a receptor for the B cell–activating cytokine, BAFF has been seen.
 Clinical Manifestation:
 Most individuals with this disease are asymptomatic.
 Because IgA is the major antibody in external secretions, mucosal defences are
weakened, and infections occur in the respiratory, gastrointestinal, and urogenital
tracts.
 Symptomatic patients commonly present with recurrent sinopulmonary infections
and diarrhoea.

D. X-LINKED LYMPHOPROLIFERATIVE SYNDROME:

 Characterized by an inability to eliminate Epstein-Barr virus (EBV), which leads to
fulminant infectious mononucleosis and development of B-cell tumors.
 Etiology:
 In 80% of cases, the disease is due to mutations in the gene for an adaptor molecule
called SLAM-associated protein (SAP)
 SAP binds to a family of cell surface molecules involved in the activation of NK cells
and T and B lymphocytes, including the Signaling Lymphocyte Activation Molecule
(SLAM).
 Defects in SAP contribute to attenuated NK and T cell activation and result in
increased susceptibility to viral infections.
 Clinical Manifestation:
 This immunodeficiency is most commonly manifested by severe EBV infection,
including severe and sometimes fatal infectious mononucleosis.

PATHOLOGY AGAM
IMMUNODEFICIENCIES ASSOCIATED WITH SYSTEMIC DISEASES
A. WISKOTT - ALDRICH SYNDROME:
 It is an X-linked Recessive disease characterized by thrombocytopenia, eczema and
marked susceptibility to infections leading to early death.
 Etiology:
 Mutation in WASP gene at Xp11.23 (encoding Wiskott - Aldrich syndrome protein)
 less levels of WASP.
 WASP links membrane receptors to cytoskeletal elements. WASP gene mutations
affect not only T lymphocytes but also the other lymphocyte subsets and platelets.
 Clinical Manifestations:
 Present with recurrent bacterial infections, eczema and bleeding caused by
thrombocytopenia.
 Thymus is normal.
 Progressive depletion of T cells in peripheral blood and in the T-cell zones.
 Increased risk of non-Hodgkin B-cell lymphomas.
 Only treatment is HSC transplantation.

B. ATAXIA TELANGIECTASIA:
 It is an autosomal-recessive disorder characterized by abnormal gait (ataxia), vascular
malformations (telangiectasia), neurologic deficits, increased incidence of tumors, and
immunodeficiency.
 Etiology:
 The gene responsible for this disorder is located on chromosome 11 and encodes a
protein called ATM (ataxia telangiectasia mutated) which is similar to
phosphatidylinositol-3 (PI-3) kinase, but is a protein kinase.
 The ATM protein is a sensor of DNA damage (double strand breaks) and it activates
p53 by phosphorylation, which in turn can activate cell cycle checkpoints and
apoptosis in cells with damaged DNA.
 Because of these abnormalities in DNA repair, the generation of antigen receptors
may be abnormal.
 Clinical Manifestations:
 Patients experience upper and lower respiratory tract bacterial infections, multiple
autoimmune phenomena, and increasingly frequent cancers with advancing age.
 The most prominent humoral immune abnormalities are defective production of
isotype switched antibodies, mainly IgA and IgG2.
 The T cell defects, are associated with thymic hypoplasia.

AGAM PATHOLOGY
SHORT NOTES
1. GRAFT VERSUS HOST DISEASE (GVHD)
Immunocompetent Immunocompromised
graft cells Attacks host cells

 Hematopoietic stem cells

 Solid organ transplants (Liver)
 Un Irradiated blood transfusion

GRAFT VERSUS HOST DISEASE (GvHD):

GvHD
Acute Chronic

 Fibrosis
 Sclerosis
Skin = Rashes  Strictures
Liver = Jaundice  Cholestasis jaundice
Intestine = Diarrhoea  Thymic abnormalities

GRAFT VERSUS LEUKEMIA EFFECT (GVL):

After allogeneic HSC transfusion

Eliminates

Donor immune cells Host leukemic cells

PATHOLOGY AGAM
2. MAJOR HISTOCOMPATIBILITY COMPLEX

 Location: Expressed on chromosome 6(6p21.3)

 Loci- A, B, C, D.
 As these were first found in Leucocytes,they are named as Human Leukocyte antigen!
 Structure: Has high Polymorphism.
 Subtypes:
 Class 1 MHC
 Class 2 MHC
 Class 3 MHC

CLASS 1 MHC GENES:

 T suppressor CD8+ cells Carries Receptor.
 Loci: HLA-A, HLA-B, HLA-C.
 Protein complex: 1,  2, 3 chains and 2 Microglobulin.
 Main functions: Graft rejection, destruction of tumor cells and virus infected cells.

CLASS 2 MHC GENES:

 T helper CD4+cells Carries Receptor.
 Locus: HLA-D
 HLA-DR,HLA-DQ,HLA-DP
 Protein complex:Alpha1, Alpha2, Beta1 and Beta2 chains
 Main function: Graft vs Host Response.

CLASS 3 MHC GENES:

 Includes Complement and Cytokines.
 Functions: organ transplants

Class 1 MHC regulates cytotoxic T cells.

Class 2 MHC regulates T helper cells.

AGAM PATHOLOGY
3. MAST CELLS
 Mast: from Greek word meaning feeding, thus Mast cells-Feeding cells.
 Mast cell was first observed by PAUL EHRLICH
 Other Names: Mastocyte, Labrocyte.
 Origin: Bone marrow derived cells that are widely distributed in the tissues.

STRUCTURE:
 Resembles basophilic Granulocytes.
 Contains:
 Histamine
 Heparin-an anticoagulant
 Leukotienes
 Platelet Activating Factor.
 Have receptors for IgE and degranulate when cross-linked with antigen.

FUNCTION:
 It acts as a receptor for IgE.
 Has Electron dense granules.
 Degranulation-Release contents when cross linked with antigen.
 Role in allergy and anaphylaxis
 Involved in wound healing, Angiogenesis, Defence against Pathogens and Blood brain
barrier functions.

MEDIATORS:
 Lysosomal enzymes
 Cytokines
 Serine Protease
 Histamine
 Serotonin
 Proteoglycan
 ATP
 Reactive Oxygen Species
 Prostaglandin and leukotrienes

PATHOLOGY AGAM
CLINICAL SIGNIFICANCE:
 Parasitic infections: Parasite(Protozoa and Helminth)
 Allergy: Asthma, Eczema, Rhinitis, Conjuctivitis.
 Anaphylaxis
 Mast cell activation Syndrome.

DIFFERENCE BETWEEN MAST CELL AND BASOPHIL STRUCTURE

MAST CELLS BASOPHIL
Larger in size Comparatively small
1000 small granules 80 Large granules
Round Nucleus Lobed nucleus

4. T LYMPHOCYTE:
 Cell Mediated Immunity. (Specific / Adaptive immunity) and delayed type of
hypersensitivity (75%-80%)
 Origin: Bone marrow
 Maturation/Differentiation: Thymus gland(It even matures further after leaving
Thymus)

STRUCTURE:
 T cell Receptor:
 Found on the surface of T cell membrane.
 Has Alpha and Beta chain region corresponds Alpha and Beta Region of MHC.
 TCR used for recognition of MHC.
 Pan T cell Markers: CD2, CD3, CD5 and CD7.

SUBTYPES:
 CD4+ T Helper cells
 CD8+Suppresor / Cytotoxic T cells
 Regulatory T cells
 Memory T cells

AGAM PATHOLOGY
Helper T cells: (60%)
 Also known as CD4 molecules
 Binds to class II molecule
 These cells are activated by cytokines.
 TH 1-elaborate IL-2 and IFN-gamma
 TH 2-elaborate IL-4, IL-5, IL-6, IL-10
 TH 17-activated by TGF-b,IL-6,IL-7,IL-23 → produces IL-17
 Function:
 Helps B cells to synthesize Antibodies
 Activates Macrophages to destroy microbes.

Suppressor / Cytotoxic cells:

 Also known as CD8 molecules
 Binds to MHC class I molecule
 Function:
 Suppress immune reaction
 Destroy antigen.

Regulatory cells:
 Small subset of CD4+T Lymphocytes.
 Function: Prevents immune reaction against self-antigen

Memory T cells:
 Antigen specific T cells.
 Stimulated on re exposure.

PATHOLOGY AGAM
5. PRIMARY AMYLOIDOSIS
 Amyloid is usually systemic in distribution and is of the AL type.
 It is the most common form of amyloidosis.
 The disorder is caused by a clonal proliferation of plasma cells that synthesize an Ig that
is prone to form amyloid due to its intrinsic physiochemical properties.
 Best defined is the occurrence of systemic amyloidosis in 5% to 15% of individuals with
multiple myeloma, a plasma-cell tumor characterized by multiple osteolytic lesions
throughout the skeletal system.
 The malignant plasma cells synthesize abnormal amounts of a single Ig (monoclonal
gammopathy), producing an M (myeloma) protein spike on serum electrophoresis.

6. BENCE JONES PROTEIN

 In addition to the synthesis of whole Ig molecules, the malignant plasma cells often
secrete free, unpaired κ or λ light chains referred to as Bence-Jones protein.
 These may be found in the serum, and due to their small molecular size, Bence-Jones
proteins are excreted and concentrated in the urine.
 In primary amyloidosis, the free light chains are not only present in serum and urine
but are also deposited in tissues as amyloid.
 However, a great majority of myeloma patients who have free light chains in serum and
urine do not develop amyloidosis.
 Clearly, not all free light chains are equally likely to produce amyloid, and it is believed
that the amyloidogenic potential of any particular light chain is largely determined by
its specific amino acid sequence.
 Most persons with AL amyloid do not have classic multiple myeloma or any other overt
B-cell neoplasm; such cases have been traditionally classified as primary amyloidosis,
because their clinical features derive from the effects of amyloid deposition without
any other associated disease.
 In virtually all such cases, however, monoclonal immunoglobulins or free light chains,
or both, can be found in the serum or urine.
 Most of these patients also have a modest increase in the number of plasma cells in the
bone marrow, which presumably secrete the precursors of AL protein.
 Thus, these patients have an underlying monoclonal proliferation of plasma cells
(monoclonal gammopathy) in which production of an abnormal protein, rather than
production of tumor masses, is the predominant manifestation.

AGAM PATHOLOGY
7. MECHANISM OF AUTOIMMUNITY
Inheritance of susceptible genes
 Incidence is greater in monozygotic twins than in dizygotic twins
 HLA genes contribute greater towards auto-immunity. (especially HLA-B27)
 Non MHC genes associated with auto immunity are:
PTPN 22 Rheumatoid arthritis PTPN 22 Mutation  Defective tyrosine
Inflammatory bowel disease phosphatise  Excessive lymphocyte activation
Type I diabetes
NOD2 Crohn Disease Defective cytoplasmic sensor of bacteria in gut.
IL2RA Multiple Sclerosis IL-2 receptor defective  Development of
effectors cells and regulation of immune
Responses affected.

Role of Infections
2 mechanisms are involved.
 Upregulation of co - stimulators of APC  when self Ag is presented, specific T-Cells
are activated in large amounts
 Cross reactivity between microbial Ag and self Ag  molecular mimicry.

Eg. Rheumatic heart disease following streptococcal infection

 Also EBV & HIV cause polyclonal B-Cells activation

 Infection  Tissue injury  structurally altered self Ag released  T-Cells activated.
 Infections  induce cytokines  may recruit self-reactive lymphocytes

8. FIBRONECTIN
 Fibronectin is a prototypical Adhesive Glycoprotein
 It is a large (450 kD) disulfide-linked heterodimer
 It exists in 2 forms:
 Tissue Fibronectin, Plasma Fibronectin
 Synthesized by: Fibroblasts, Monocytes, Endothelium
 Fibronectin has specific domains that can bind to distinct
Extra Cellular Matrix (ECM) components (e.g., collagen, fibrin,
heparin, and proteoglycans), as well as integrins
 In healing wounds, tissue & plasma Fibronectin provide the
scaffolding for subsequent ECM deposition, angiogenesis, and
re-epithelialization.

PATHOLOGY AGAM
9. ACUTE PHASE REACTANTS
 A variety of Acute phase reactant proteins (APR) are released in plasma in response to
tissue trauma & infection
 APR are synthesized in Liver & Macrophage
 Their Major role is to protect the Normal cells from harmful effects of toxic molecules
generated in inflammation & to clear waste materials away
 Deficient of APR leads to severe form of diseases in the form of chronic & repeated
inflammatory response

EXAMPLES:
 Transport proteins
 Ceruloplasmin
 Haptoglobin
 Cellular protein factors
 alpha 1 antitrypsin
 alpha 1 chymotrypsin
 alpha 2 antiplasmin
 Plasminogen activator Inhibitor
 Coagulation proteins
 Fibrinogen
 Plasminogen
 Von willebrand Factor
 Factor VIII
 Anti-oxidants
 Ceruloplasmin
 Stress proteins
 Hsp
 Ubiquitin
 Immune agents
 Serum Amyloid A & P component
 C - Reactive Protein (CRP)

AGAM PATHOLOGY
10. HYPER IgM SYNDROME
 In this disorder, the affected patient make IgM antibodies, but deficient in their ability
to produce IgG, IgA, IgE antibodies
 More common in Male than Female
 Defective in B cell Antibody Class Switching → defective lymphocyte Activation &
Function
 It is now known that defect in this disease affects the ability of helper T cells to deliver
activating signals to B Cells & Macrophages

FORMS:
 X Linked Recessive (70%)
 Mutation in gene encoding CD40L located on xq26
 Autosomal Recessive
 Loss of function mutation involving either CD40 or enzyme called activation
induced cytidine deaminase (AID) a DNA editing enzyme that is required for IgG
class switching & maturation

CLINICAL FINDINGS:
 Increased IgM antibodies
 Decreased IgE, IgA, IgG antibodies
 Number of B & T cell Normal

CLINICAL FEATURES:
 Recurrent pyogenic infections, because the level of opsonizing IgG antibody is low
 Mutation with CD40L are susceptible to pneumonia (Pneumocystis jiroveci)
 Occasionally, the IgM antibodies react with blood cells, giving rise to autoimmune
hemolytic anemia, thrombocytopenia, and neutropenia

PATHOLOGY AGAM
VERY SHORT NOTES
1. SITES OF BIOPSY OF AMYLOIDOSIS
The diagnosis of Amyloidosis depends on the histologic demonstration of amyloid
deposit in tissue
 Renal Biopsy
 Rectal Biopsy
 Gingival tissues
 Abdominal Fat aspirates (commonly used )
 Sural Nerve Biopsy
 Skin Biopsy

2. STAINING CHARACTER OF AMYLOIDOSIS

 H & E : Amorphous, Eosinophilic, Hyaline, Extracellular substance
 Congo red:
 Ordinary Light Microscope : Pink / Red color
 Polarizing Microscope : Green birefringence
 Methyl / crystal violet : Metachromatic (Rose Pink)
 Thioflavin S&T : UV Light (Fluorescence)

3. SAGO SPLEEN
 Grossly,
 Splenic enlargement is not marked and cut surface shows characteristic translucent
pale and waxy nodules resembling sago grains and hence the name.
 Microscopically,
 The amyloid deposits begin in the walls of the arterioles of the white pulp and may
subsequently extend out and replace the follicles.

4. CHRONIC GRANULOMATOUS DISEASE

 Chronic Granulomatous Disease is characterized by defects in Bacterial Killing & render
patient susceptible to recurrent Bacterial infections
 Due to: inherited defects in gene encoding components of phagocyte oxidase, the
phagolysosomal enzyme that generates superoxide
 Most common Varients:
 X linked: defect in membrane bound components (gp91phox)
 Autosomal recessive: defects in gene encoding two of the cytoplasmic components
(p47phox and p67phox).
 This often leads to collection of activated macrophages that wall off the microbes,
forming granulomas
AGAM PATHOLOGY
5. MORPHOLOGY OF SPLEEN IN SLE
 Splenomegaly
 Capsular thickening
 Follicular hyperplasia
 Onion skin lesions - Central penicilliary arteries may show concentric intimal and
smooth muscle cell hyperplasia .

6. AMYLOID REACTION
 The histologic diagnosis of amyloid is based on its staining characteristics.
 The most common staining technique uses the dye Congo red, which under ordinary
light imparts a pink or red colour to amyloid deposits.
 Under polarized light the Congo red-stained amyloid shows so-called apple-green
birefringence.
 This reaction is shared by all forms of amyloid and is caused by the crossed β-pleated
configuration of amyloid fibrils.
 Confirmation can be obtained by electron microscopy, which reveals amorphous non
oriented thin fibrils.
 AA, AL, and ATTR types of amyloid can also be distinguished by specific immuno
histochemical staining.

7. LE PHENOMENON
In the pathogenesis of SLE, Autoantibodies specific for red cells, white cells, and
platelets opsonize these cells and promote their phagocytosis and lysis.

 ANAs, which are involved in immune complex formation, cannot penetrate intact cells.
But if cell nuclei are exposed, however, the ANAs can bind to them.
 In tissues, nuclei of damaged cells react with ANAs, lose their chromatin pattern, and
become homogeneous, to produce so-called LE bodies or hematoxylin bodies.
 Related to this LE phenomenon is the LE cell, which is readily seen when blood is
agitated in vitro.
 The LE cell is any phagocytic leukocyte (blood neutrophil or macrophage) that has
engulfed the denatured nucleus of an injured cell.
 The demonstration of LE cells in vitro was used in the past as a test for SLE.
 With new techniques for detection of ANAs, this test is now largely of historical
interest.
 Sometimes, LE cells are found in pericardial or pleural effusions in patients.

PATHOLOGY AGAM
8. NATURAL KILLER CELLS-CYTOTOXIC LYMPHOCYTES
 Structure:Large and Granular cytoplasm
 Surface molecule CD16 CD56
 Function:
 Plays a major role in host rejection of tumor and viral infected cells.
 NATURAL KILLER CELLS induce APOPTOSIS in virus-infected or tumour cells.

9. ANTINUCLEAR ANTIBODIES
They are directed against various nuclear antigens including DNA, RNA and proteins
(all together called generic ANAs) and can be grouped into different categories

Anti-nuclear Antibodies Antigen recognized Clinical Utility

Anti-dsDNA DNA (double- High titers of IgG antibodies are SLE-
stranded) specific (but not to single-stranded DNA
Anti-Sm Non histone proteins Specific to SLE; don’t correlate with
bound to RNA disease activity or clinical manifestations
Ant histone antibodies Histones associated More frequent in drug induced lupus
with DNA than SLE
Antibodies to DNA Multiple nuclear Best screening test; if repeated test are
negative, SLE unlikely
Anti-Ro (SS-A) RNP (Ribo Nucleo Not specific for SLE; predictive value
Protein) indicates increased risk for neonatal
lupus and SICCA syndrome

10. CYTOKINES
Cytokines are soluble proteins, peptides and glycoprotein.

CLASSIFICATION:
 Haematopoietin family
 G-CSF,GM-CSF, Erythropoietin, Thrombopoietin, Interleukin 2,3,4,5,6,7,9
 Chemokines family: Interleukin 8, MCP, NAP, PF.
 Others: TNF, PDGF, TGF.

STRUCTURE: Cytokine receptors

 Immunoglobulin superfamily
 Haematopoetic growth factor type 1 Receptor family
 IFN type 2 Receptor family
 TNF Receptor family
 Transmembrane helix Receptor family.

AGAM PATHOLOGY
UPDATES:
1. INNATE LYMPHOID CELLS:
 Innate lymphoid cells (ILCs) are tissue-resident lymphocytes that lack T-cell antigen
receptors and cannot respond to antigens
 They instead are activated by cytokines and other mediators produced at sites of tissue
damage.
 They are thought to be sources of inflammatory cytokines during early phases of
immune reactions.
 ILCs are classified into groups based on the dominant cytokines they produce:
 Group 1 ILC producing Th1 cells
 Group 2 ILC producing Th2 cells
 Group 3 ILC producing Th17 cells

2. INTERFERONOPATHIES
 RIG-like receptors (RLRs), named after the founding member RIG-I (retinoic acid-
inducible gene-I)
 Cytosolic receptors for microbial DNA (RLRs) are often derived from viruses in the cell
 They activate a pathway called STING (for stimulator of interferon genes), which leads
to the production of the antiviral cytokine interferon-α.
 Excessive activation of the STING pathway causes systemic inflammatory disorders
collectively called interferonopathies.

3. ROLE OF CHARCOT LAYDEN CRYSTALS IN ALLERGIC REACTIONS:

 Eosniophils contain crystals called Charcot-Leyden crystals composed of the protein
galectin-10
 These crystals are sometimes released into the extracellular space and can be detected
in the sputum of patients with asthma.
 These crystals promote inflammation and enhance Th2 responses, so they may
contribute to allergic reactions.

6. RESERVOIRS OF HIV
 Infected T follicular helper cells in the germinal centers are also reservoirs of HIV.
 Since CTLs are largely excluded from germinal centers, these viral reservoirs cannot be
readily eliminated by the host immune response.

PATHOLOGY AGAM
5. HYPER ACUTE REJECTION
 Hyperacute rejection is mediated by preformed antibodies specific for antigens on graft
endothelial cells.
 The preformed antibodies may be natural IgM antibodies specific for blood group
antigens, or may be antibodies specific for allogeneic MHC molecules that were
induced by prior exposure of the organ recipient to allogeneic cells through blood
transfusions, pregnancy, or transplantation of another organ.
 Immediately after the graft is implanted and blood flow is restored, the antibodies
bind to antigens on the graft vascular endothelium and activate the complement
system, leading to endothelial injury, thrombosis, and ischemic necrosis of the graft
 Hyperacute rejection is rare because every donor and recipient are matched for blood
type, and potential recipients are tested for antibodies against the cells of the
prospective donor, a test called a cross-match.
 Histology: Virtually all arterioles and arteries exhibit acute fibrinoid necrosis of their
walls and narrowing or complete occlusion of their lumens by thrombi

6. HAND
 The clinical syndrome of CNS abnormalities is called HIV-associated neurocognitive
disorder (HAND).
 It is believed that HIV is carried into the brain by both infected T cells and monocytes
(Robbins 9th edition: HIV is carried to brain by only monocytes – HIV isolates in brain
are exclusively M-tropic)

7. ONE LINERS
 PD-1 receptor, an inhibitory receptor responsible for anergy, binds to two ligands, PD-
L1 and PD-L2 that are expressed on a wide variety of cells.
 Endotheliitis (vascular pattern of acute cellular rejection) is also called intimal arteritis
 Chronic rejection manifests as interstitial fibrosis and gradual narrowing of graft blood
vessels (graft arteriosclerosis)
 Mutations affecting Th1 responses are associated with atypical mycobacterial
infections; the syndrome is called Mendelian susceptibility to mycobacterial disease.

AGAM PATHOLOGY
CLICK HERE FOR FEEDBACK

PATHOLOGY AGAM