Immunopathology

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Immunopathology

• Dr. Amitabha Basu MD

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OUR TOPIC

1. TRANSPLANT REJECTION
2. Graft Vs Host disease
3. AUTOIMMUNE DISEASES

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TRANSPLANT REJECTION and MHC matching
Type of graft. Mechanism of rejection. Graft
survival. Complication of immunosuppression. Manag
ement. Graft Vs Host reaction.
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Type of Grafts

1. Allograft An organ or tissue transplanted from
   one individual to another of the same species,
   i.e. human to human.
2. Auto graft Tissue that is taken from one site
   and grafted to another site on the same person
   "skin from his thigh replaced the burned skin on
   his arms
3. Xenograft A xenograft is a transplantation of
   tissue from a donor of one species to a recipient
   of another species
4. Fetal tissue grafts Less chance of reaction.

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Mechanism of allograft rejection

• T cell mediated reaction
• Involve Cytotoxic T cell ( CD8)
• Type IV hypersensitivity reaction
• Antibody mediated reaction
• (mainly ADCC).

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When you give a graft..

• The organ contain
• Tissues of the organ
• Some lymphocytes of the donor
• Some macrophage (APC) of the donor

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In the direct pathway,

• Donor class I and class II antigens on APC of
  the graft are recognized by CD8 cytotoxic T
  cells and CD4 helper T cells of host.
• CD4 cells? cytokines? tissue damage by a local
  delayed hypersensitivity reaction.
• CD8 T cells? kill graft cells

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In the indirect pathway

1. Activate macrophage tissue damage.
2. Form antigen antibody complex and produce
   vasculitis tissue damage.

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Types of rejection reaction

1. Hyper acute rejection
2. Acute rejection
3. Chronic rejection

Hyper acute ? Acute rejection ? Chronic rejection ?
Minutes to hours Within months Years
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Hyperacute rejection

• Hyperacute rejection occurs when preformed
  antidonor antibodies are present in the
  circulation of the recipient.
• Morphology shrunken liver, necrotic swollen
  tubular epithelial cell, may show pyknotic
  nuclei.
• Scanty bloody urine.

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Transplant reaction
Hyper acute rejection Antibody mediated. localized Arthus reaction Fibrinoid necrosis of arterioles, thrombus in vessels Neutrophils in the area.
Acute rejection 1. Acute cellular rejection. CD4 and CD8 cell in tissue.
Acute rejection rejection vasculitis 2. Acute Humoral rejection. Necrotizing Vasculitis. And Neutrophils in the tissue.
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Chronic Rejection Antibody mediated vascular damage Vascular intimal proliferation.
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Kidney change
Hyper acute rejection kidney rapidly becomes cyanotic, mottled, and flaccid and may excrete a mere few drops of bloody urine. Swollen necrotic epithelial cells.
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Management

• Drug cyclosporine (block nuclear factor of
  activated T cells- thus inhibit the gene for
  IL-2).
• Monoclonal anti-T-cell antibodies (e.g.,
  monoclonal anti-CD3 and antibodies against the
  IL-2 receptor a chain).

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Methods of Increasing Graft Survival

• HLA ( both Class I and class II antigen)
  matching in transplants.
• Immunosuppressive therapy.

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Survival of grafts HLA matching in transplants

• HLA matching ( of donor and recipient cells) for
  both class I and class II antigens improves
  survival

MHC
MHC
Good

Donor
R
MHC
MHC

Bad
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Immunosuppressive therapy

• As a method of graft survival
• What are the risks?

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Complications of Global Immunosuppression

• Opportunistic infections

Pneumocystis Carinii Sliver stain.
Cytomegalovirus (CMV)
pseudohyphae Candida
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Candida (C. albicans ) infection
Location skin, mouth, gastrointestinal tract,
and vagina . Risk DM and immuno compromised
patient. Presentation (thrush-oral).
Gray-white, dirty-looking pseudomembranes
composed of matted organisms and inflammatory
debris ,
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Others

• Risk for developing EBV-induced lymphomas,
• Human papillomavirus-induced squamous cell
  carcinomas, and
• Kaposi sarcoma

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Transplantation of Hematopoietic Cells

• Develop Graft vs host reaction.
• GVH disease occurs in any situation in which
  immunologically competent cells are transplanted
  into immunologically crippled recipients.
• Example bone marrow, whole blood.

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Mechanism

• Results from the donor lymphocytes attacking the
  recipient tissues that has offending HLA
  antigens.

Lymphocyte of donor CD8 cells
Host tissue
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Types

• Acute days to week
• Donor cells infiltrate hosts epithelia, liver,
  bile duct , Gut, lymphnode and dysfunction them.
• Infection CMV
• Clinical Jaundice, skin rash, bloody diarrhea,
  hepatomegaly heavy infiltration of lymphocytes in
  the host tissue.

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d/d of acute type of GVH

• Transfusion reaction (TR)
• in contract to GVH, TR occur immediately after
  transfusing a mismatched blood.
• ( if you donate A blood to a person with B
  blood group etc)

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Types

• Chronic skin atrophy and cholestatic jaundice.

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C/FGVH disease Jaundice and Rash,
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Time for Autoimmunity
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Topic

1. Immune tolerance
2. Termination of tolerance
3. Definition AUTOIMMUNITY
4. Mechanisms proposed for development of
   autoimmunity
5. Mediators
6. Autoantibody
7. Diseases

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Immune tolerance

• A state of unresponsiveness to a specific antigen
  or group of antigens to which a person is
  normally responsive.
• Self tolerance Immune tolerance against self-
  antigen.

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(No Transcript)
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Termination of tolerance

• X-irradiation
• Immunization with cross reactive antigens.
• Autoimmune diseases.

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AUTOIMMUNITY 

• Autoimmunity can be defined as breakdown of
  mechanisms responsible for self tolerance.

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Mechanisms proposed for development of
autoimmunity include
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1. Failure of activation induced death of self
   reactive T cell.

Self reactive T cell
So these T cells kills the cell of our body in
spite they contain self antigen.
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Mechanisms proposed for development of
autoimmunity include

• Molecular mimicry Some cells of our body
  share similar antigen like that of microbes, when
  antibodies produced to kill these microbes , they
  destroy cells of the body also.

Host cell
bacteria
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Termination of tolerance examples (nice to know)
Molecular mimicry In Streptococcus infection and EBV infections. Rheumatoid arthritis, Rheumatic Heart disease.
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Mediators

• Cytokines.
• Compliments.

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Cytokines

• Interleukins
• TNF-alpha
• Interferons

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Few examples

• IL-1, TNF-a, type 1 interferons IL-6 innate
  immunity
• IL-2 Growth factor for T-cells
• IL-12 and IFN-? involved in both innate and
  adaptive immunity
• IL-10 and TGF-ß down-regulate immune responses

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Cytokines induce their effects in three ways

• Autocrine effect IL-2 produced by
  antigen-stimulated T cells stimulates the growth
  of the same cells
• Paracrine effect IL-7 produced by bone marrow or
  thymic stromal cells promotes the maturation of
  B-cell progenitors in the marrow or T-cell
  precursors in the thymus, respectively
• Endocrine effect IL-1 and TNF- produce the
  systemic acute-phase response during
  inflammation.
• Acute Inflammatory effect IL1 and IL8.

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Autoantibody

• Definition Antibody against self antigen.
• Mainly against various component of Nuclei.
• These are celled Antinuclear Antibodies (ANA).

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ANA DETECTION

1. By estimation of serum titer
2. By staining pattern the tissue.

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Disease
ANA
Staining pattern
SLE Rim and diffuse dsDNA
MCTD Speckled Anti-RNP
PSS (Scleroderma) Nucleolar Scl-70
CREST syndrome Centro mere anti Centro- mere antibody
Sjogren's syndrome SS-A SS-B
Inflammatory myopathy Jo-1
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SLE
Diffuse and Rim
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Systemic Lupus Erythematosus (SLE)

1. Skin rash - Malar or discoid
2. Sensitivity to light (photo dermatitis)
3. Serositis/synovitis - inflammation of serosal
   surfaces along with effusions

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Typical skin lesion in SLE
An immunofluorescence micrograph stained for IgG
reveals deposits of immunoglobulin along the
dermal-epidermal junction.
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SLE

1. Glomerulonephritis Lupus nephritis Nephrotic
   syndrome .
2. Cytopenias - anemia, leucopenia,
   thrombocytopenia.
3. Heart Libman-Sachs Endocarditis
4. Thrombosis - Antiphospholipid syndrome (APS) can
   occur in patients with SLE.
5. Splenomegaly periarteriolar fibrosis ("onion
   skinning") .

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SLE

• Arthritis, fever, weight loss.
• Vasculitis with fibrinoid necrosis.

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Lupus nephritis Wire loop lesion. Deposit of
C1q occur.
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Chronic Discoid Lupus Erythematosus

• Less severe.
• Skin plaques showing varying degrees of edema,
  erythema, scaliness.
• Diagnosis positive ANA test, but dsDNA are
  rarely present.

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Drug induced lupus

• Hydralazine, procainamide, INH, and
  D-penicillamine.
• Diagnoses
• Positive antihistone antibodies.
• Negative (mostly( dsDNA).

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Diagnosis SLE

• Antinuclear antibody - rim pattern, anti double
  stranded-DNA.
• Decreased serum complement - especially C1q.

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Staining patterns in Autoimmune disease.
Nucleolar (PSS)
Speckled MCTD
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Scleroderma

• Progressive Systemic Sclerosis, PSS
• Limited scleroderma, or CREST syndrome.

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Scleroderma (Progressive Systemic Sclerosis, PSS)

• Def Characterized by excessive fibrosis in a
  variety of tissues due to collagen deposition.
• About 75 of cases are in women, mostly middle
  aged.
• Patient may have hypertension.

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Scleroderma dermal fibrosis no adenexa seen
Positive for Scl-70
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Scleroderma reduced figure and limb movements.
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Important clinical feature in PSS

• Skin thickening by fibrosis and collagen
  deposition.
• Malignant Hypertension
• And difficulty in swallowing.

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Limited scleroderma, or CREST syndrome

• Positive for anti-Centro mere antibody.
• C Calcinosis in skin and elsewhere.
• R Raynaud's phenomenon, sensitivity to
  cold.
• E Esophageal dysmotility from sub mucosal
  fibrosis.
• S Sclerodactyly from dermal fibrosis.
• T Telangiectasias .

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Calcinosis in skin
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Early gangrenous necrosis from vasospasm with
Raynaud's phenomenon.
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Sclerodactyly from dermal fibrosis
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Features PSS CREST
Collagen Deposition Initial skin involvement wide spread Limited areas, like face and fingers
Visceral involvement Early and common Late and not common
Course of disease Rapid Benign
Frequent features Wide spread Skin involvement, malignant Hypertension and difficulty in swallowing. CREST
Prognosis Bad Better / benign course
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Sjogren's syndrome

• Autoimmune disease that involves-
• Salivary glands (with xerostomia) and
• Lacrimal glands (with xerophthalmia).
• Most patients are middle-aged women.

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Sjogren's syndrome salivary gland histopathology
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Diagnosis ANA in Sjogren's syndrome

• The auto antibodies SS-A (Ro) and SS-B (La).

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Sicca syndrome

• Isolated Autoimmune destruction of salivary and
  Lacrimal glands.
• This is not common.
• Same ANAs are present like Sjogren syndrome (SS-A
  and SS-B)

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Inflammatory myopathy

• Polymyositis
• Common in women
• Associate with visceral cancer.
• Symmetric weak-ness of the large muscles.
  (difficulty in getting up from the chair/climbing
  steps)
• DIAGNOSIS Jo-1 autoantibody

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Dermatomyositis ( skin muscle weakness)

• Clinical feature Heliotrope Rash

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PRIMARY IMMUNODEFICIENCY SYNDROMES

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PRIMARY IMMUNODEFICIENCY SYNDROMES

1. Congenital B- cell deficiency
2. X-linked Agammaglobulinemia of Bruton
3. Selective IgA Deficiency
4. Common Variable Immunodeficiency
5. Congenital T- cell deficiency
6. DiGeorge Syndrome
7. Wiskott-Aldrich Syndrome
8. Congenital Both B cell and T cell deficiency
9. Severe Combined Immunodeficiency

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Key words Pathophysiology
Bruton Disease Defect in Humoral immunity B cell defect. Intact CMI. Tyrosine kinase deficiency.
DiGeorge Syndrome Thymic hypoplasia and T cell defect. Deletion of Chromosome 22q
Wiskott-Aldrich Syndrome Thymus normal present with viral and fungal infection. Thrombocytopenia, eczema
SCID Both Humoral and cell mediated depressed. Adenosine deaminase deficiency.
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X-Linked Agammaglobulinemia of Bruton

• Abnormal Ig due to lack of light chain ( abnormal
  B cell) low Ig in serum.
• Seen after 6 months.
• Infection H. influenzae, S. pneumoniae.
• Pathogenesis lack of opsonization by Ig but
  opsonization by complement may be normal.
• No germinal center in LN.
• Polio vaccination may produce disease!

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X-linked Agammaglobulinemia of Bruton

• C/F Chronic pharyngitis, sinusitis infection
  with bacterial organisms (Hemophilus,
  Staphylococcus).
• More in male.
• Rarely infection with Virus( because of intact T
  cell immunity).

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Common Variable Immunodeficiency

• Relatively common a heterogeneous group of
  disorders with low Igs.
• They have normal B cell, but they do not
  differentiated to plasma cells.

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Selective IgA Deficiency most common

• Incidence1 in 700
• Asymptomatic.
• Virtual lack of circulating IgA as well as
  secretory IgA.
• Increased risk for respiratory, gastrointestinal
  (diarrhea).

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Severe Combined Immunodeficiency (SCID)

• Autosomal recessive Adenosine deaminase
  deficiency. (50 )
• No IgM or IgA
• Ineffective B/T cell.

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Severe Combined Immunodeficiency (SCID)

• Morphology
• Lympnnode and Thymic atrophy can occur.

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Severe Combined Immunodeficiency

• Some patients develop a skin rash
• shortly after birth owing to transplacental
  transfer of maternal T cells or,
• by a blood transfusion that cause GVH disease.

• Infants develop
• Candida skin rashes and thrush,
• Persistent diarrhea, severe respiratory tract
  infections
• Pneumocystis carinii and Pseudomonas soon after
  birth.

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Wiskott-Aldrich Syndrome

• Def Immunodeficiency with Thrombocytopenia and
  Eczema.
• X-linked recessive disease thrombocytopenia,
  eczema, and recurrent infection, ending in early
  death.

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DiGeorge Syndrome

• Age Children
• Etiology Deletion on the long arm of chromosome
  22.
• Pathogenesis
• Markedly decreased numbers of circulating T
  lymphocytes and Thymic hypoplasia.
• T-cell deficiency that results from failure of
  development of the third and fourth pharyngeal
  pouches

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DiGeorge Syndrome Clinical manifestation CATCH
22

• C Cardiac defect
• A Abnormal facies
• T Thymic hypoplasia
• C Cleft palate
• H Hypocalcemia

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DiGeorge Syndrome Clinical features

• Susceptible to fungal and viral infections.
  Defective mandible.

Deletion of chromosome 22.
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Key words clinical features
Bruton Disease Occur after 6 months. Commonly bacterial Infection No viral, fungal infection
DiGeorge Syndrome Thymus hypoplasia, viral, fungal infection common.
SCID Thymus and lymph node atrophy, all types of infections (both bacterial and viral)
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Thank you.