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					Immunopathology




Dr. Amitabha Basu MD
            OUR TOPIC
1.   TRANSPLANT REJECTION
2.   Graft Vs Host disease
3.   AUTOIMMUNE DISEASES
 TRANSPLANT REJECTION and MHC matching

Type of graft.
Mechanism of rejection.
Graft survival.
Complication of
immunosuppression.
Management.
Graft Vs Host reaction.
                  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.
 Mechanism of allograft rejection
1. T cell mediated reaction
  a. Involve Cytotoxic T cell ( CD8+)
  b. Type IV hypersensitivity reaction


2. Antibody mediated reaction
 (mainly ADCC).
    When you give a graft…..
• The organ contain
  – Tissues of the organ
  – Some lymphocytes of the donor
  – Some macrophage (APC) of the donor
          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
      In the indirect pathway
1. Activate macrophage= tissue damage.

2. Form antigen antibody complex and
   produce vasculitis= tissue damage.
    Types of rejection reaction
1. Hyper acute rejection
2. Acute rejection:
3. Chronic rejection

Hyper acute   Acute rejection    Chronic
    ↓                ↓          rejection
                                    ↓
 Minutes to   Within months       Years
   hours
        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.
              Transplant reaction
Hyper acute       Antibody     Fibrinoid necrosis of
rejection         mediated.    arterioles, thrombus in
                  [localized   vessels
                  Arthus       Neutrophils in the area.
                  reaction]
Acute rejection   1. Acute     CD4+ and CD8+ cell in
                  cellular     tissue.
                  rejection.
Acute             2. Acute     Necrotizing Vasculitis.
rejection=        Humoral      And Neutrophils in the
rejection         rejection.   tissue.
vasculitis
 Chronic    Antibody mediated   Vascular intimal
Rejection    vascular damage     proliferation.
              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.
              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 α chain).
 Methods of Increasing Graft Survival

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

• Immunosuppressive therapy.
  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
       Donor        R       =   Good
       MHC         MHC
                           = Bad
Immunosuppressive therapy
    As a method of graft survival

        What are the risks?
    Complications of Global Immunosuppression

 Opportunistic infections:




Pneumocystis     Cytomegalovirus   pseudohyphae
    Carinii          (CMV)           : Candida
 Sliver stain.
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 ,
                Others
• Risk for developing EBV-induced
  lymphomas,

• Human papillomavirus-induced squamous
  cell carcinomas, and

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



                                      Lymphocyte of
 Host                                    donor
tissue
                                       [CD8+ cells]
                      Types
• Acute – days to week
  – Donor cells infiltrate host’s 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.
     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)
                  Types

• Chronic – skin atrophy and cholestatic
  jaundice.
C/F=GVH disease : Jaundice and Rash,
Time for Autoimmunity
                 Topic
1. Immune tolerance
2. Termination of tolerance
3. Definition: AUTOIMMUNITY
4. Mechanisms proposed for development of
   autoimmunity
5. Mediators
6. Autoantibody
7. Diseases
         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.
    Termination of tolerance

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

• Autoimmunity can be defined as
  breakdown of mechanisms responsible
  for self tolerance.
 Mechanisms proposed for development of
         autoimmunity include:       2
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.
  Mechanisms proposed for development of
          autoimmunity include:
2.     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
      Termination of tolerance :
       examples (nice to know)
Molecular mimicry:         Rheumatoid
In Streptococcus infection arthritis, Rheumatic
and EBV infections.        Heart disease.
             Mediators
• Cytokines.
• Compliments.
                 Cytokines
• Interleukins
• TNF-alpha
• Interferons
            Few examples
• IL-1, TNF-α, type 1 interferons & IL-6:
  innate immunity
• IL-2 : Growth factor for T-cells
• IL-12 and IFN-γ: involved in both innate
  and adaptive immunity
• IL-10 and TGF-β: down-regulate immune
  responses
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.
             Autoantibody
• Definition : Antibody against “self
  antigen”.
• Mainly against various component of
  Nuclei.

• These are celled : Antinuclear Antibodies
  (ANA).
          ANA DETECTION
A. By estimation of serum titer
B. By staining pattern the tissue.
   Disease      Staining pattern          ANA
SLE              Rim and diffuse   dsDNA
MCTD             Speckled          Anti-RNP
PSS              Nucleolar         Scl-70
(Scleroderma)
CREST            Centro mere       anti Centro-
syndrome                           mere antibody
Sjogren's                          SS-A & SS-B
syndrome
Inflammatory                       Jo-1
myopathy
    SLE




Diffuse and Rim
  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
Typical skin lesion in SLE




         An immunofluorescence micrograph
         stained for IgG reveals deposits of
         immunoglobulin along
         the dermal-epidermal junction.
                      SLE
4. Glomerulonephritis – Lupus nephritis =
   Nephrotic syndrome .
5. *Cytopenias - anemia, leucopenia,
   thrombocytopenia.
6. Heart: Libman-Sachs Endocarditis
7. Thrombosis - Antiphospholipid syndrome
   (APS) can occur in patients with SLE.
8. Splenomegaly: periarteriolar fibrosis ("onion
   skinning") .
                   SLE
• *Arthritis, fever, weight loss.

• Vasculitis – with fibrinoid necrosis.
Lupus nephritis : Wire loop lesion. Deposit of
                   C1q occur.
 Chronic Discoid Lupus Erythematosus
• Less severe.

• Skin plaques showing varying
  degrees of edema, erythema,
  scaliness.

• Diagnosis: positive ANA test, but
  dsDNA are rarely present.
         Drug induced lupus
• Hydralazine, procainamide, INH, and D-
  penicillamine.

• Diagnoses:
  – Positive antihistone antibodies.
  – Negative (mostly( dsDNA).
            Diagnosis SLE
1. Antinuclear antibody - rim pattern, anti
   double stranded-DNA.
2. Decreased serum complement -
   especially C1q.
Staining patterns in Autoimmune disease.




    Nucleolar                  Speckled
      (PSS)                     MCTD
               Scleroderma

1.   Progressive Systemic Sclerosis, PSS
2.   Limited scleroderma, or CREST
     syndrome.
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.
  Scleroderma: dermal fibrosis: no
           adenexa seen




Positive for Scl-70
Scleroderma ; reduced figure and
       limb movements.
Important clinical feature in PSS

• Skin thickening by fibrosis and collagen
  deposition.
• Malignant Hypertension
• And difficulty in swallowing.
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 .
Calcinosis in skin
Early gangrenous necrosis from vasospasm
      with Raynaud's phenomenon.
Sclerodactyly from dermal
        fibrosis
 Features              PSS                  CREST
Collagen           Initial skin   Limited areas,
Deposition     involvement : wide like face and
                                  fingers
                     spread
Visceral      Early and common         Late and not
involvement                            common
Course of     Rapid                    Benign
disease
Frequent      Wide spread Skin          CREST
features      involvement, malignant
              Hypertension and
              difficulty in swallowing.
Prognosis                 Bad            Better / benign
                                             course
        Sjogren's syndrome
• Autoimmune disease that involves:-
1. Salivary glands (with xerostomia)
   and
2. Lacrimal glands (with
   xerophthalmia).

•   Most patients are middle-aged women.
Sjogren's syndrome; salivary gland
          histopathology
    Diagnosis ; ANA in Sjogren's
             syndrome
• The auto antibodies SS-A (Ro) and SS-B
  (La).
             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)
      Inflammatory myopathy
 Polymyositis
1. Common in women
2. Associate with visceral cancer.
3. Symmetric weak-ness of the large
   muscles. (difficulty in getting up from the
   chair/climbing steps)
4. DIAGNOSIS: Jo-1 autoantibody
  Dermatomyositis ( skin + muscle
          weakness)
• Clinical feature: Heliotrope Rash
PRIMARY IMMUNODEFICIENCY SYNDROMES
     PRIMARY IMMUNODEFICIENCY
            SYNDROMES

1. Congenital B- cell deficiency:
     1. X-linked Agammaglobulinemia of Bruton
     2. Selective IgA Deficiency
     3. Common Variable Immunodeficiency
2. Congenital T- cell deficiency
     1. DiGeorge Syndrome
     2. Wiskott-Aldrich Syndrome

3. Congenital Both B cell and T cell deficiency
     1. Severe Combined Immunodeficiency
     Key words ; Pathophysiology
Bruton     Defect in Humoral immunity: B cell defect.
Disease    Intact CMI.
           Tyrosine kinase deficiency.
DiGeorge   Thymic hypoplasia and T cell defect.
Syndrome   Deletion of Chromosome 22q
Wiskott-   Thymus normal: present with viral and
Aldrich    fungal infection. Thrombocytopenia,
Syndrome   eczema
SCID       Both Humoral and cell mediated
           depressed.
           Adenosine deaminase deficiency.
  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!
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).
 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.
 Selective IgA Deficiency: most common

• Incidence:1 in 700
• Asymptomatic.
• Virtual lack of circulating IgA as well as
  secretory IgA.
• Increased risk for respiratory,
  gastrointestinal (diarrhea).
    Severe Combined Immunodeficiency
                 (SCID)

•    Autosomal recessive: Adenosine
     deaminase deficiency. (50 %)
    1. No IgM or IgA
    2. Ineffective B/T cell.
  Severe Combined Immunodeficiency
               (SCID)


Morphology:
   Lympnnode and Thymic atrophy can occur.
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
1. Candida skin rashes and thrush,
2. Persistent diarrhea, severe respiratory tract infections
3. Pneumocystis carinii and Pseudomonas soon after birth.
      Wiskott-Aldrich Syndrome

• Def: Immunodeficiency with
  Thrombocytopenia and Eczema.

• X-linked recessive disease :
  thrombocytopenia, eczema, and recurrent
  infection, ending in early death.
         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
DiGeorge Syndrome : Clinical manifestation
               CATCH 22


C = Cardiac defect
A = Abnormal facies
T = Thymic hypoplasia
C = Cleft palate
H = Hypocalcemia
    DiGeorge Syndrome : Clinical
             features
• Susceptible to fungal and viral infections.
  Defective mandible.


                    Deletion
                    of chromosome 22.
       Key words: clinical features
Bruton      Occur after 6 months.
Disease     Commonly bacterial Infection
            No viral, fungal infection
DiGeorge    Thymus hypoplasia, viral, fungal infection
Syndrome    common.

SCID        Thymus and lymph node atrophy, all types
            of infections (both bacterial and viral)
Thank you.

				
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posted:10/9/2011
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