Immune

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					Diseases of IMMUNITY




                       1
               OBJECTIVES
I) Differentiate between the concepts of “Innate”
   and “Adaptive” immunity
II) Visually recognize and understand the basic
   roles of lymphocytes, macrophages, dendritic
   cells, NK cells
III) Understand the roles of the major cytokines
   in immunity
IV) Differentiate and give examples of the four (4)
   different types of hypersensitivity reactions


                                                 2
                   OBJECTIVES
 V) Know the common features of autoimmune diseases, and the
  usual four (4) main features :
                   1) Etiology
                   2) Pathogenesis
                   3) Morphology
                   4) & clinical examination
of :         1) Systemic Lupus Erythematosus,
             2) Rheumatoid Arthritis,
             3) Sjögrens, Systemic Sclerosis (Scleroderma),
             4) Mixed Connective Tissue Disease, and
             5) “Poly-” (aka, “Peri-”) -arteritis Nodosa
 VI) Differentiate between
                       1)Primary (Genetic) and
                       2)Secondary (Acquired) Immunodeficiencies

                                                               3
             OBJECTIVES
VII) Understand the usual four (4) main
  features of AIDS, i.e., etiology,
  pathogenesis, morphology, clinical
  expression
VIII) Understand the usual four (4) main
  features of Amyloidosis



                                           4
           IMMUNITY
• INNATE (present before birth,
  “NATURAL”)
• ADAPTIVE (developed by
  exposure to pathogens, or in a
  broader sense, antigens)


                                   5
          INNATE IMMUNITY
I) BARRIERS
II) CELLS:        1) LYMPHOCYTES,
                   2) MACROPHAGES,
                   3) PLASMA CELLS,
                   4) NK CELLS
III) CYTOKINES / CHEMOKINES
IV) PLASMA PROTEINS: Complement, Coagulation
   Factors
V) Toll- Like Receptors, TLR’s


                                               6
Toll - like receptors (TLRs) are :
A class of single membrane-spanning non-catalytic
receptors that recognize structurally conserved
molecules derived from microbes once they have
breached physical barriers such as the skin or
intestinal tract mucosa , and activate immune cell
responses.




                                                 7
 Major Histocompatibility Complex (MHC)

• A genetic “LOCUS” on Chromosome 6, which
  codes for cell surface compatibility
• Also called HLA (Human Leukocyte Antigens)
  in humans and H-2 in mice
• It’s major job is to make sure all self cell
  antigens are recognized and “tolerated”,
  because the general rule of the immune system
  is that all UN-recognized cells will NOT be
  tolerated


                                             8
     ADAPTIVE IMMUNITY

• CELLULAR, i.e., direct cellular
  reactions to antigens

• HUMORAL, i.e., antibodies


                                    9
10
 CELLS of the IMMUNE SYSTEM
1) LYMPHOCYTES, T
2) LYMPHOCYTES, B
3) PLASMA CELLS (MODIFIED B CELLS)
4) MACROPHAGES, aka “HISTIOCYTES”, (APCs,
 i.e., Antigen Presenting Cells)
5) “DENDRITIC” CELLS (APCs, i.e., Antigen
 Presenting Cells)
6) NK (NATURAL KILLER) CELLS


                                       11
LYMPHOCYTES

              12
13
ANY ROUND CELL WITH RATHER
DENSE STAINING CYTOPLASM AND
MINIMAL CYTOPLASM IN
CONNECTIVE TISSUE, A BIT BIGGER
THAN AN RBC, IS A
          LYMPHOCYTE
   …UNTIL PROVEN OTHERWISE


                              14
MACROPHAGE
   aka
HISTIOCYTE
             15
MACROPHAGES are MONOCYTES
that have come out of circulation
and have gone into tissue


                                    16
MACROPHAGES, TEM, SEM



                        17
ANY CELL MIXED IN WITH LYMPHOCYTES BUT HAS A
LARGER MORE “OPEN”, LESS DENSE, LESS
CIRCULAR NUCLEUS WITH MORE CYTOPLASM IS A
                MACROPHAGE
          …UNTIL PROVEN OTHERWISE
ALMOST ALL “GRANULAR” or “PIGMENTED” CELLS IN
CONNECTIVE TISSUE ARE MACROPHAGES.
GRANULOMAS, GIANT CELLS, ARE CHIEFLY
MACROPHAGES ALSO.



                                               18
                     PLASMA CELLS




1) ROUND NUCLEUS
2) OVOID CYTOPLASM
3) PERIPHERAL CHROMATIN
4) “CLEAR ZONE” BETWEEN NUCLEUS AND WIDER LIP OF
CYTOPLASM



                                                   19
20
NK CELLS

           21
  GENERAL SCHEME of CELLULAR EVENTS

• APCs (Macrophages, Dendritic Cells)
• T-Cells (Control Everything)
   – CD4 “REGULATORS” (Helper)
   – CD8 “EFFECTORS”
• B-Cells Plasma Cells AB’s
• NK Cells



                                         22
             CYTOKINES
1) MEDIATE INNATE (NATURAL) IMMUNITY, IL-1,
 TNF, INTERFERONS
2) REGULATE LYMPHOCYTE GROWTH (many
 interleukins, ILs)
3) ACTIVATE INFLAMMATORY CELLS
4) STIMULATE HEMATOPOESIS, (CSFs, or
 Colony Stimulating Factors)



                                         23
     CYTOKINES / CHEMOKINES
• CYTOKINES are PROTEINS produced by
  MANY cells, but usually LYMPHOCYTES and
  MACROPHAGES, numerous roles in acute
  and chronic inflammation, AND immunity
   – TNF, IL-1, by macrophages
• CHEMOKINES are small proteins which are
  attractants for PMNs



                                            24
 ( MHC ) Major Histocompatibility Complex
• A genetic “LOCUS” on Chromosome 6, which codes for
  cell surface compatibility
• Also called HLA (Human Leukocyte Antigens) in humans
  and H-2 in mice
• It’s major job is to make sure all self cell antigens are
  recognized and “tolerated”, because the general rule of
  the immune system is that all UN-recognized cells will
  NOT be tolerated




                                                        25
 MHC MOLECULES (Gene Products)
• I (All nucleated cells and platelets), cell
  surface glycoproteins, ANTIGENS
• II (APC’s, i.e., macs and dendritics, lymphs),
  cell surface glycoproteins, ANTIGENS
• III Complement System Proteins




                                              26
      IMMUNE SYSTEM DISORDERS
        WHAT CAN GO WRONG?

I) HYPERSENSITIVITY REACTIONS, I-IV
II) “AUTO”-IMMUNE DISEASES, aka
 “COLLAGEN” DISEASES (BAD TERM)
III) IMMUNE DEFICIENCY SYNDROMES, IDS:
       - PRIMARY (GENETIC)
       - SECONDARY (ACQUIRED)



                                         27
 HYPERSENSITIVITY REACTIONS (4)

  I- (Immediate Hypersensitivity)
 II- (Antibody Mediated Hypersensitivity)
III- (Immune-Complex Mediated Hypersensitivity)

IV- (Cell-Mediated Hypersensitivity)




                                                  28
Type I - IMMEDIATE HYPERSENSITIVITY
• “Immediate” means seconds to minutes
• “Immediate Allergic Reactions”, which may lead to
  anaphylaxis, shock, edema, dyspnea death
   – 1) Allergen exposure
   – 2) IMMEDIATE phase: MAST cell DEgranulation,
     vasodilatation, vascular leakage, smooth muscle
     spasm
   – 3) LATE phase (hours, days): Eosinophils, PMNs, T-
     Cells




                                                     29
            TYPE II - HYPERSENSITIVITY
          (ANTIBODY MEDIATED IMMUNITY)

• ABs attach to cell surfaces
   1- OPSONIZATION ‫(الطهى‬basting ‫ يطرى اللحم‬the turkey)
   2- PHAGOCYTOSIS
   3- COMPLEMENT FIXATION (cascade of C1q, C1r,
     C1s, C2, C3, C4, C5….. )
   4- LYSIS (destruction of cells by rupturing or
     breaking of the cell membrane)




                                                          30
       TYPE II DISEASES
- Autoimmune Hemolytic Anemia, (AHA)
- Idiopathic Thrombocytopenic Purpura, (ITP)
- Goodpasture Syndrome (Nephritis and Lung
   hemorrhage)
- Rheumatic Fever
- Myasthenia Gravis
- Graves Disease
- Pernicious Anemia, (PA)


                                               31
        TYPE III - HYPERSENSITIVITY
       IMMUNE COMPLEX MEDIATED
1) Antigen/Antibody “Complexes”
2) Where do they go?
  - Kidney (Glomerular Basement Membrane)
  - Blood Vessels
  - Skin
  - Joints
3) Common Type III Diseases-
    - SLE (Lupus),
    - Poly (Peri) arteritis Nodosa,
    - Poststreptococcal Glomerulonephritis,
    - Arthus reaction (hrs),
    - Serum sickness (days)


                                              32
 TYPE IV - HYPERSENSITIVITY - CELL-MEDIATED (T-CELL)
               DELAYED HYPERSENSITIVITY

• Tuberculin Skin Reaction




• DIRECT ANTIGENCELL CONTACT
  – GRANULOMA FORMATION
  – CONTACT DERMATITIS



                                                   33
                  SUMMARY
I     Acute allergic reaction
II    Antibodies directed against cell surfaces
III   Immune complexes
IV    Delayed Hypersensitivity, e.g., Tb skin test




                                                 34
    RENAL TRANSPLANT REJECTION

• HYPERACUTE (minutes) : AG/AB reaction of
  vascular endothelium
• ACUTE (days months): cellular
  (INTERSTITIAL infiltrate) and humoral
  (VASCULITIS)
• CHRONIC (months): slow vascular fibrosis



                                             35
ACUTE CELLULAR (T)         ACUTE HUMORAL




                 CHRONIC                   36
      AUTO-IMMUNE DISEASES
1- Failure of SELF RECOGNITION
2- Failure of SELF TOLERANCE
3- TOLERANCE
    a- CENTRAL (Death of self reactive lymphocytes)
    b- PERIPHERAL (anergy, suppression by T-cells, deletion by
       apoptosis, sequestration (Ag masking))
4- STRONG GENETIC PREDISPOSITION
5- OFTEN RELATED TO OTHER AUTOIMMUNE DISEASES
6- OFTEN TRIGGERED BY INFECTIONS

          Auto – immune D:       systemic OR       local


                                                                 37
CLASSIC AUTOIMMUNE DISEASES (SYSTEMIC)

1- LUPUS (SLE) Systemic Lupus Erythematosus
2- RHEUMATOID ARTHRITIS
3- SJÖGREN SYNDROME
4- SYSTEMIC SCLEROSIS (scleroderma)
5- “collagen” diseases (term no longer used)



                                           38
CLASSIC AUTOIMMUNE DISEASES (LOCAL)
 1- HASHIMOTO THYROIDITIS
 2- AUTOIMMUNE HEMOLYTIC ANEMIA
 3- MULTIPLE SCLEROSIS
 4- AUTOIMMUNE ORCHITIS
 5- GOODPASTURE SYNDROME
 6- AUTOIMMUNE THROMBOCYTOPENIA
 7- “PERNICIOUS” ANEMIA
 8- INSULIN DEPENDENT DIABETES MELLITUS
 9- MYASTHENIA GRAVIS
 10- GRAVES DISEASE




                                          39
             N.B.

• The list of diseases proven to
  be “autoimmune” grows by
  leaps and bounds every year !



                                   40
                 LUPUS (SLE)
1 -Etiology: Antibodies (ABs) directed against the patient’s
   own DNA, HISTONES, NON- histone RNA, and
   NUCLEOLUS
2- Pathogenesis: Progressive DEPOSITION and
   INFLAMMATION to immune deposits, in skin, joints,
   kidneys, vessels, heart, CNS
3 -Morphology: “Butterfly” rash, skin deposits,
   glomerolunephritis (NOT discoid)
4 -Clinical expression: Progressive renal and vascular
   disease, POSITIVE A.N.A.

                                                         41
42
H   R
O   I
M   M
O


    N
    U
    C
S
    L
P   E
E   O

C   L
    A
K   43
    R
            SLE, GLOMERULUS   44
SLE, SKIN
Libman -Sacks vegetations, also called Libman -
Sacks endocarditis




                                                  45
     TABLE 6-10 -- Clinical and Pathologic Manifestations of Systemic Lupus
                                 Erythematosus
          Clinical Manifestation               Prevalence in Patients, %
Hematologic                                              100
Arthritis                                                 90
Skin                                                      85
Fever                                                     83
Fatigue                                                   81
Weight loss                                               63
Renal                                                     50
Central nervous system                                    50
Pleuritis                                                 46
Myalgia                                                   33
Pericarditis                                              25
Gastrointestinal                                          21
Raynaud phenomenon                                        20
Ocular                                                    15
Peripheral neuropathy                                     14

                                                                           46
  MORE AUTOIMMUNE DISEASES
• RHEUMATOID ARTHRITIS
• SJÖGREN SYNDROME
• SCLERODERMA (SYSTEMIC
  SCLEROSIS)




                             47
48
               SJÖGREN SYNDROME
Keratoconjunctivitis “sicca” (i.e., “dry” is another name for Sjögren Syndrome




                                                                          49
50
           SCLERODERMA (SYSTEMIC SCLEROSIS)

Scleroderma is progressive small vessel vasculitis and fibrosis. Auto-
antibodies have always been difficult to find.




                                                                         51
   SYSTEMIC SCLEROSIS (SCLERODERMA)
This is a classical hand appearance of scleroderma, i.e., systemic sclerosis.


                                                                                52
MORE AUTOIMMUNE DISEASES (LOCAL)
-HASHIMOTO THYROIDITIS
-AUTOIMMUNE HEMOLYTIC ANEMIA
-MULTIPLE SCLEROSIS
-AUTOIMMUNE ORCHITIS
-GOODPASTURE SYNDROME
-AUTOIMMUNE THROMBOCYTOPENIA
-“PERNICIOUS” ANEMIA
-INSULIN DEPENDENT DIABETES MELLITUS (I)
-MYASTHENIA GRAVIS
-GRAVES DISEASE




                                           53
   IMMUNODEFICIENCIES
• PRIMARY (GENETIC)
• SECONDARY (ACQUIRED)



                         54
               PRIMARY
- CHILDREN with repeated, often severe infections,
   cellular AND/OR humoral problems
- BRUTON (X-linked agammaglobulinemia)
- COMMON VARIABLE
- IgA deficiency
- Hyper IgM
- DIGEORGE (THYMIC HYPOPLASIA) 22q11.2
- SCID (Severe Combined Immuno Deficiency)
- ….with thrombocytopenia and eczema (WISKOTT-
   ALDRICH)
- COMPLEMENT DEFICIENCIES

                                                     55
• 22q11.2 deletion syndrome, also known as Velocardiofacial
  Syndrome, DiGeorge Syndrome and Strong Syndrome is a disorder
  caused by the deletion of a small piece of chromosomes 22. The
  deletion occurs near the middle of the chromosome at a location
  designated q11.2. It has a prevalence estimated at 1:4000
• SCID: Chronic diarrhea, ear infections, recurrent Pneumocystis
  jirovecii pneumonia, and profuse oral candidiasis commonly occur.
  These babies, if untreated, usually die within 1 year due to severe,
  recurrent infections. However, treatment options are much improved
  since David Vetter, “the Bot in the Bubble”.
• Wiskott -Aldrich syndrome (WAS) is a rare X-linked recessive
  disease characterized by eczema, thrombocytopenia (low
  platelet count), immune deficiency, and bloody diarrhea
  (secondary to the thrombocytopenia). It is also sometimes called the
  eczema-thrombocytopenia-immunodeficiency syndrome



                                                                    56
ADA=
ADENOSINE
DEAMINASE




            57
              TABLE 6-11 -- Examples of Infections in Immunodeficiencies
Pathogen                                                       Granulocyte   Complement
  Type            T-Cell-Defect             B-Cell Defect         Defect        Defect
Bacteria         Bacterial sepsis           Streptococci,     Staphylococci,  Neisserial
                                           staphylococci,     Pseudomonas infections, other
                                            Haemophilus                        pyogenic
                                                                               bacterial
                                                                              infections

 Viruses    Cytomegalovirus, Epstein-       Enteroviral
                 Barr virus, severe         encephalitis
                 varicella, chronic
            infections with respiratory
               and intestinal viruses


Fungi and    Candida, Pneumocystis        Severe intestinal     Candida,
parasites            carinii                 giardiasis         Nocardia,
                                                               Aspergillus

 Special    Aggressive disease with          Recurrent
features    opportunistic pathogens,      sinopulmonary
            failure to clear infections     infections,
                                          sepsis, chronic
                                            meningitis


                                                                                         58
          AIDS (SECONDARY IDS)
•   Etiology: HIV
•   Pathogenesis: Infection, Latency, Progressive T-Cell loss
•   Morphology:
•   Clinical Expressions: Infections, Neoplasms,
    Progressive Immune Failure, Death, HIV+, HIV-RNA (Viral
    Load)



                                                                59
       EPIDEMIOLOGY
• HOMOSEXUAL (40%, and declining)
• INTRAVENOUS DRUG USAGE (25%)
• HETEROSEXUAL SEX (10% and rising)




                                  60
ETIOLOGY




           61
      PATHOGENESIS




ATTACHING       BUDDING


                          62
        PATHOGENESIS




LATE BUDDING
                       EARLY BUDDING




                       MATURE NEW VIRIONS



                                       63
   REVERSE TRANSCRIPTASE
• The enzyme reverse transcriptase (RT) is
  used by retroviruses to transcribe their
  single-stranded RNA genome into single-
  stranded DNA and to subsequently
  construct a complementary strand of DNA,
  providing a DNA double helix capable of
  integration into host cell chromosomes.



                                             64
PATHOGENESIS

               65
  PATHOGENESIS
1) PRIMARY INFECTION
2) LYMPHOID INFECTION
3) ACUTE SYNDROME
4) IMMUNE RESPONSE
5) LATENCY
6) AIDS




                        66
67
 GENERAL IMMUNE ABNORMALITIES

• LYMPHOPENIA

• DECREASED T-CELL FUNCTION

• B-CELL ACTIVATION, POLYCLONAL

• ALTERED MONOCYTE/MACROPHAGE FUNCTION



                                         68
        INFECTIONS
• Protozoal / Helminthic: Cryptosporidium,
  PCP (Pneumocystis Carinii Pneumonia),
  Toxoplasmosis
• Fungal: Candida, and the usual 3
• Bacterial: TB, Nocardia, Salmonella
• Viral: CMV, HSV, VZ


                                        69
• Cryptosporidium is a protozoan
  pathogen of the Phylum Apicomplexa and
  causes a diarrheal illness called
  cryptosporidosis.




                                       70
PCP

      71
CRYPTOSPORIDIUM
                  72
CASEATING GRANULOMA


                      73
      CANCERS of AIDS

•   KAPOSI SARCOMA
•   B-CELL LYMPHOMAS
•   CNS LYMPHOMAS
•   CERVIX CANCER, SQUAMOUS CELL




                                   74
      AMYLOIDOSIS
• BUILDUP OF AMYLOID “PROTEIN”
   – AL (Amyloid Light Chain)
   – AA (NON-immunoglobulin protein)
   – Aß (Alzheimer’s)
• WHERE? BLOOD VESSEL WALLS, at first
   – KIDNEY
   – SPLEEN
   – LIVER
   – HEART

                                        75
CONGO RED STAIN, WITHOUT, and WITH, POLARIZATION



                                              76
       AMYLOID ASSOCIATIONS
• PLASMA CELL “DYSCRASIAS”, i.e., MULTIPLE
  MYELOMA
• CHRONIC GRANULOMATOUS DISEASE, e.g., TB
• HEMODIALYSIS
• HEREDOFAMILIAL
• LOCALIZED
• ENDOCRINE MEAs (Multiple Endocrine Adenomas)
• AGING




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