4.2 Immunity

Qbank - recall/Core/Pathology/4.2 Immunity

// 4.2 Immunity

10.07.21 | 13:15 tags:


Hypersensitivity Reaction

  • The immune system inititates collateral damage

Gel Coombs Classification:

Type I Hypersensitivity Reaction

1. Sensitization

  • Antigen is internalized by APC
  • Antigen is presented to the Th2 T-cell (CD4+)
  • T-Cell Activation occurs
  • Production of cytokines:
    • IL-4 - Secretion of IgE and B-cell activation
    • IL-5 - Recruitment of Eosinophils
    • IL-13 - Mucus secretion
  • The produced IgE attaches to mast cell IgE cross-link receptor modifying it
    • No symptoms in this phase

2. Re-exposure

  • Upon antigen re-entry, the IgE attches to the antigen which then cross-links with Mast cells that were modified
  • This causes degranulation and release of chemicals
    • Acute/Pre-formed/Early Phase
      • These chemicals are pre-formed and are released immediately
      • They include chemicals such as
        • Histamines
        • Protease
        • Eosinophil Chemotactic Factor
    • Late phase
      • AA-metabolites
        • LT4s - causes bronchospasm
        • PG2s - esp. PGB2
      • Cytokines
        • TNF-alpha
        • IL-1
        • IL-4
        • IL-5
        • IL-13

[[Pasted image 20210715225858.png]]

  • Casoni’s test is historical

mnemonic: A - B - C - D

Type II Hypersensitivity Reaction

Also known as Ab mediated HSR/Cytocytic HSR

Type 1Type 2
IgE played the roleIgG or IgM plays the role
Presence of antigens on surface of tissues

Mechanisms

Opsonization

[[Pasted image 20210716012037.png]]

Examples:

  • Mismatch b Blood Transfusion Reaction
  • Erythroblastosis Fetalis
  • Autoimmune hemolytic anemia
  • Autoimmune thrombocytopenia
  • Autoimmune leucopenia

Inflammation

  • The antigen-antibody complex activates complement system C3a/C5a
  • Neutrophili/macrophages chemotoxis
  • Leads to Tissue damage
  • Examples
    • Acute Rheumatic Fever
      • The antigen of bacteria (strep.) is similar to cardiac tissue and joints
      • the antibodies produced against these antigens attack this
    • ANCA-mediated Vasculitis
      • ANCA - Anti-neutrophilic Cytoplasmic Antibodies
    • Goodpasture syndrome
      • Goodpasture syndrome also referred to as anti-glomerular basement membrane (anti-GBM) disease, is an autoimmune disease that affects both the kidneys and lungs by the formation of autoantibodies that attack their basement membranes
      • The non-helical protruding part of non-collagenous chain is the antigen against which antibodies are formed
      • Good- Glomerular
      • Pasture- Pulmonary
    • Pemphigus vulgaris
      • Epidermal cells are attaked
      • Presents as bullaes
    • Ocular Cicatricial Pemphigoid

Cellular Dysfunction

  • The presence of antibodies lead to Cellular Dysfunction
  • This was also know as Type V hypersensitivity reaction
  • An antibody stimulates a receptor
    • e.g Graves Disease 1
      • Leading cause for hyperthyroidism
    • Myasthenia Gravis 2
      • Antibody against Acetyl choline
    • Pernicious anemia
      • Intrinisic factor due to abnormal antibodies
    • Insulin resistant Diabetes melitus
      • Antibodies againt insulin receptor
MneomicCondition
MyMyasthenia gravis
BloodBlood transfusion, erythroblastis fetalis
GroupGraves disease, Goodpasture syndrome
IsImmune Hemolytic Anemia, thrombocytopenia, leucopenia, insulin resistance
RRheumatic fever
HHyperacute graft rejection
PositivePernincious anemia, Pemphigus vulgaris, Ocular Cicatricial Pemphigoid

Type III Hypersensitivity

  • Also known as Immune Complex Disease

Phase I: Formation of antigen-antibody complexes

  • Takes about 5-7 days
  • Antigen entry -> Antibody formation -> Antigen-antibody binding

Phase II : Deposition of immune complexes

  • Immune complexes are deposited in tissue, especially blood vessels → initiation of complement cascade → release of lysosomal enzymes from neutrophilscell deathinflammationvasculitis

  • Deposition occurs in ultafiltration organs et. cetera

  • e.g:

    • Kidney - glomerulonephritis
    • Serosa
    • Lymph Nodes - such as lymphadenopathy
    • Skin
    • Synovium
  • 10-14 days lag time

  • Thus it’s also known as Delayed Type Hypersensitivity

  • Immune-complexes that are medium sized are the most dangerous

    • small ones are non-pathogenic
    • large ones result in acute manifestations with lagsss
MnemonicCondition
SSys. Lupus Eryth., Serum Sickness
HHenoch schonlein purpura (HSP)
AARTHUS reaction [Localized Type III]
RReactive arthritis, Lepra Type II reaction
PPost. streptococcal glomerulonephritis, Polyarteritis Nodosa

In Acute SLE:

  • Serum C3 levels is reduced due to excessive activation of complement cascade indicative of active disease

Hypersensitivity reactions - AMBOSS

ARTHUS: This reaction is usually encountered in experimental settings following the injection of antigens (in vaccines)

Seen as fibrinoid necrosis 1. Cell Injury

  • plasma cells deposition and endothelial cell damage
  • Neutrophilic inflitration occurs such as

Hypersensitivity IV Reaction

  • This is CELL MEDIATED hypersensitivity and not antibodies
  • CD4+ T-cell involvement
    • Leads to Delayed Type Hypersensitivity
    • Antigen presents to APC
    • Activates Th1 or Th17
      • When IFN-gamma is secreted -> IFN-gamma -> Th1 cell
      • When IL-1, IL-6, IL-23 is secreted -> Th17 activation -> Memory cell
      • On re-exposure:
        • Th1 cell production increases
        • Lymphoctoxin increases
        • Macrophage activation
        • Formation of Granuloma
      • Primary Th1 activation -> more macrophages are seen in granuloma
      • Primary Th17 activation -> more neutrophilic infiltration

Tuberculin test/Mantoux test

  • 0.1ml purified protein derivative of mycobacterium microbe is given into forearm intradermal
  • in non-exposed individuals, it leads to formation of antibodies
  • however in exposed indivduals, it is re-exposure, thus forming granulomas and swelling
  • Thus after 72 hours, measurement of the induration
  • It is a check of if the person has been exposed to mycobacteria AND if immune system is working Lepromin test
  • Similar principle

Examples of CD4 involvement

Mnemonic
RRheumatoid
Aarthritis - collagen or citruline
MMultiple sclerois
ChecksContact Dermatitis
ifInflammatory Bowel Disease
purePsoriasis
DMTDiabetes melitus (subtype 1 - one cause of many)
LeadsLeprosy
To TruthTuberculosis

CD-8 T-cell

[[Pasted image 20210716234647.png]]

  • Examples:
    • Graft rejection (not hyperacute)
    • Virus and tumor infected cells
      • NK-cells also kill them the difference is:
        • Dependence on MHC class I for CD8+ cell
        • NK cell does MHC independent killing
        • HBV and HBC
    • Type 1 Diabetes - CTLs (Cytotoxic T- lymphocytes) damage pancreatic beta cells -> insulitis
    • CD8 T+ also secrete IFN-gamma

[[Pasted image 20210726195225.png]]

Tolerance

  • It is the response to self-antigens

  • The unresponsiveness of an organism’s immune system to antigens that are expressed by the organism’s own cells. There are two types of mechanisms of immune tolerance: central (e.g., negative selection of T cells) and peripheral (e.g., suppression of lymphocyte activation).

  • When this property is lost -> autoimmune disorders

  • Two types

1. Central Tolerance

  • Occurs in thymus, bone marrow - sites of T/B-cell proliferation

[[Pasted image 20210717202250.png]]

Negative selection

  • Occurs in the medulla for T-cells and Bone Marrow for B cells
    • Dendritic cells and medullary epithelial cells in the thymus express a wide array of self-antigens to test the T-cell and when binded, apoptosis
    • AIRE is responsible for expression of some subtypes of antigens
  • Normally self-reactive both B/T cells are killed off through clonal deletion
    • This is via apoptosis
  • AIRE gene codes for autoimmune regulator
  • Mutations cause type 1 autoimmune polyendocrine syndrome
    • Thyroidism
    • Adrenal
    • Candida
  • Location: thymic medulla
  • Tests if T cells bind to tissue-restricted self-antigens presented on MHC by thymic medullary cells
    • T cells that do not bind receive survival signal.
    • T cells that bind self-antigens undergo apoptosis, except for a few that become regulatory T cells.
  • Self-antigen presentation is mediated by the autoimmune regulator protein (AIRE protein), dysfunction of which can lead to:

“Life is ACHe without AIRE”: Autoimmune regulator protein (AIRE) dysfunction can lead to Adrenal insufficiency, chronic mucocutaneous Candidiasis, and Hypoparathyroidism.

Receptor editing

  • Occurs in Bone marrow, only for B-Cell
  • In this, an attempt to change the specificity of the antigen receptor of self reactive immature B-cells, in order to rescue them from apoptosis occurs.
  • Same test of self-antigen expression by dendritic cells occurs
  • RAG genes will be reexpressed which allows editing of immunoglobulin thus modifying binding affinity
  • If not, it contunues to apoptosis

Peripheral Tolerance

  • Occurs in lymph nodes, spleen, systemic circulation

Anergy

  • This is the functional hyporesponsiveness to self-antigens
  • Most self antigens do not induce co-stimulatory signals
  • These self-antigens produce
    • Increased CTLA-4
    • Increased PD-1
    • These molecules are negative co-stimulatory signal generating molecules
    • Cancer cells also preferentially attach to negative co-stimulatory signal generating
      • New class of anti-cancer drugs are targetting this
  • T-cell anergy - Decreased Interaction between B7(CD80/86) and CD-28
  • B-Cell Anergy -Decreased Interaction between CD40 and CD40L

T-Regulatory Cells

These are CD4+ CD25+ FOXp3+ cells

  • Especially seen in development of normal fetus inside pregnant mother (acceptance of fetus)
  • T-reg cells secrete Anti-inflammatory cytokines - IL-10 and TGF-beta
    • IL-10 inhibits expression of ***MHC Class II ***and B7
  • It expresses CTLA-4 and PD-1 - decreased activation of B and T cell
  • T-reg cells have Interleukin-2 receptor alpha chain (CD25) essential for normal functioning
    • Polymporphism of IL-2RA/ CD25 leads to Multiple Sclerosis (one of many causes)
    • IPEX syndrome - FOXp3 3
Mnemonic
IImmune dysfunction
PPolyendocrinopathy
EEnteropathy
XX-linked disease

Antigen Sequestration

  • Immune-privilege site - antigens are hidden/sequestered

    • B: Brain - except Area postrema/ Chemoreceptor Trigger Zone (CTZ)
    • E: Eye - except optic nerve
    • T: Testes - except epididymis
  • When trauma occurs to these tissues, exposure to antigens occurs and thus antibodies are formed

    • e.gL Orchitis, Opthalmitis

Deletion of Self-reactive B/T-cells

  • Repeated attachment to antigen without co-stimulatory signals lead to apoptosis
  • Higher expression of FAS-Ligand of self reactive T and B cells
    • Defective FasL and FAS (CD95) leads to autoimmunle lymphoproliferative syndrome
      • A - Anemias, thrombocytopenias
      • L - Lymph adenopathy
      • P -
      • S - Spleenomegaly
      • Leads to Lymphoma eventually
    • 1. Cell Injury
    • BIM is able to directly activate Bax/Bak to cause permeabilization of the outer mitochondrial membrane and induce apoptosis. In contrast to AICD, the killing of antigen-activated T cells during shutdown of an immune response to an acute infection requires Bim, but not Fas

Autoimmune Disorders

Genetic Factors

  • Failure of Tolerance as seen above
  • HLA gene defect
    • HLA-B27 - Ankylosing spondylitis
  • Non-HLA Genes
    • PTPN-22 gene defect
      • This is responsible for controlled lymphocyte proliferation
      • Defect leads to uncontrolled proliferation with loss of tolerance
      • Mutation is gain of function
    • NOD gene defect
      • NOD acts as a pattern recognizer (and is vital for commensal GI bacteria’s existence)
      • Inflammatory Bowel Disease - NOT A CLASSICAL AUTOIMMUNE DISORDER
    • IL-2R gene defect
      • Leads to Multiple sclerosis
      • Type 1 Diabetes Mellitus

Infections

Mechanisms:

  • Increased costimulatory signals -> excessive APC activation
  • Molecular mimicry
    • Seen in rheumatic fever
    • Strep antigen antibodies attack host tissue due to similarity
    • May also lead to spreading of cryptic epitope
      • A cryptic epitope is defined as a hidden or sequestered epitope that is processed and presented more efficiently as a result of an inflammatory immune response initiated by either a dominant epitope, as in a response to an infectious agent, or revealed as a result of the diversification of the response secondary to self tissue damage, as in an autoimmune response.
        • Hidden Ag is exposed
      • It is seen in multiple AI disorders including Rheumatic Heart Disease (Rheumatic fever)
      • EPITOPE SPREADING is the reason for Overlapping Features
  • Polyclonal B-cell Activation
    • Done by HIV and EBV
    • Due to excessive induction of proliferation of B cells, there’s higher chances of autoimmune self-reactive B-cells to form

[[Pasted image 20210717193638.png]]

Miscellaneous

  • Hormones
    • Estrogen and progestrone
    • Estrogen reduces apoptosis of self-reactive B cells
  • UV-light
    • esp. in SLE
  • Release of sequestered antigens
  • Drugs: esp -
    • S: Sulfonamide
    • H: Hydralzine
    • I: Isoniazid
    • P: Procainamide

Trigger is very very vital

  • Enviromental trigger in genetically susceptible individuals is the most likely etiology
  • There is increased incidence in twins
  • Environmental triggers lead to bystander activation or molecular mimicry
    • Bystander activation is the activation of T cells specific for an antigen X during an immune response against antigen Y . May occur during viral infections.

Systemic Lupus Erythematatous

  • This is a chronic, systemic autoimmune disease
    • Presents as flares and remissions are common
    • More common in Middle-aged females, esp. African American and Hispanic (10:1 female to male)
      • As noted before, estrogen reduces apoptosis of self-reactive B cells
    • Occurs in children too (2:1 female to male) - lesser female bias
  • It is a multisystem disorder

[[Pasted image 20210718003135.png]]

  • Type III Hypersensitivity Disorder - + Secondary Type II in blood

    • Poorly formed apoptotic debris, such as from UV light, activates self reactive lymphocytes, which then produce antibodies against the host nuclear antigen
    • These antigen-antibody complexes are initially at low levels, but when taken up by APCs such as dendritic cells, DNA antigens activate Toll-like receptors (TLRs) -> IFN-alpha -> amplification
    • This leads to higher number of Ag-Ab complexes and these deposit in the tissue
    • Usually this is cleared out by the complement cascade (classical pathway)
    • C1 -> C4 -> C4bC2b -> C4bC2b3b [C3 convertase]
      • Thus Early Complement Protein [C1q, C4, C2] deficiency is associated with 50% risk of developing Lupus.
        • Most common deficiency is of C2
      • CH50 an indicator of classical pathway is reduced
  • Any tissue can be involved

  • Clinical Features

    • Fever, weight loss, fatigue
      • Inflammatory and non-specific
    • lymphadenopathy
      • due to excessive activation of immune system
      • Non-specific
    • Raynaud phenomenon
      • Change in color of finger sequentially due to a problem that causes decreased blood flow to the fingers.
      • Here due to loss of blood supply -> white fingers
      • Over time due to ischemia -> blue fingers esp. when exposed to cold, stress
      • Return of blood -> red esp. when exposed to hot
      • It is again non-specific
    • Malar butterfly rash - acute cutaneous lupus

      • Occurs on exposure to sunlight
      • It is non-specific but very relevant
      • Due to degeneration of basal layer of epidermal layer due to antibodies present in dermo-epidermal layer

      [[Pasted image 20210717223506.png]]

    • Discoid rash - chronic cutaneous lupus
      • It is the reason lupus got it’s named due to it’s wolf-bite like lesion

    [[Pasted image 20210717225906.png]] 3. Oral or nasopharyngeal ulcers - painless 4. Arthritis - Non-erosive - No deformity - Most common feature 5. Serositis - Pleuritis - Shrinking lung syndrome (smaller diaphragm) - Pleural effusion maybe seen - Pericarditis - 6. Psychosis or seizures 7. Renal damage - Nephritic Syndrome - Diffuse proliferaltive glomerulonephritis (Tyoe IV GN) - Most common - Nephrotic Syndrome - Membranous glomerulonephritis - Combination of both - No damage at all - Other features: - Wire loop lesions - Due to subendothelial emmune complex deposition 8. Anemia, thrombocytpoenia or leukopenia from Type II hypersensitive reaction - Associated with Auto Ab [10%] and anemia of chronic disease [60%] 9. Libman-sacks endocarditis [vegetations on both sides of the valve] - Different from normal endocarditis as it is only one side in such endocarditis - Lower surface is predominantly involved [LSE - Lower surface] - Vegetations are fibrins and platelets - SLE -> LSE (mnemonic) 10. Anti-nuclear antibody (ANA) - Mosr sensitive but not specific - As it may also be seen in other AI diseases and is also present in 5% of population 11. Anti-dsDNA or Anti-Sm (Smith) are highly specific - Anti-dsDNA is prognostic - It is associated with disease activity and renal nephritis - Relapse can also be tested

    • Antiphospholipid antibody is also associated with SLE (one-third of patients).
      • These are due to cryptic epitope exposure of phospholipids due to antibody attack on proteins attached to phospholipis
      • Anticardiolipin -
        • False positive VDRL and RPR - syphilis screening test as they look for anticardiolipin antibodies and the reagent is cardiolipin
        • Thus lupus coagulant is tested for viaDRVVT - Dilute Russel Viper Venom Test
      • Lupus Anticoagulant
        • False PTT increased time
      • Anti-Beta2-glycoprotein I

Antiphospholipid antibody syndrome is characterized by hypercoagulable state due to antiphospholipid antibodies (especially lupus anticoagulant).

  • Results in arterial and venous thrombosis including deep venous, hepatic vein, placental (recurrent pregnancy loss), and cerebral (stroke) thrombosis
  • Requires ==lifelong anticoagulation ==
  • Associated with SLE; however, more commonly occurs as a primary disorder - SLE is a secondary cause of APLA

[[Pasted image 20210718003303.png]]

  • Non scarring alopecia (hair loss) is not associated to nutritional deficiency
  • Direct coomb’s test in absence of hemolytic anemia

Standalone criteria:

  • Biopsy proven Lupus Nephritis + positive for ANA or anti-dsDNA Ab

Full House Phenomenon:

  • All types of antibodies are seen in the biopsy

Misc organs affected:

[[Pasted image 20210718005008.png]]

In Drug Induced lupus, anti-histone antibodies are formed

  • S - Sulfanamide
  • H - Hydralazine
  • I - Isoniazid
  • P - Procainamide ANA (antinuclear antibody is positive by definition
  • Removal of drug usually results in remission
  • CNS and Renal involvement is very rare

Treatment for SLE is

  • Avoid exposure to sunlight
  • Glucocorticoids for flares
  • Other immunosuppressive agents in severe and refractory disease

Renal failure, infections and accelerated coronary atherosclerosis (late onset) are common causes of death

Cellular morphology that may be seen

LE Cell ANA damages nuclear chromatin

  • The cell which results from this is called Lupus Erythematosus body
  • Neutrophils and macrophages phagocytize leads to formation of LE Cell
    • Denatured nuclear material is present
  • Its also present in Rheumatoid arthritis and drug induced lupus Historically, LE Cell was used to diagnose SLE, however it no longer is.

[[Pasted image 20210718180840.png]]

TART cell

  • A granulocyte that has engulfed the nucleus of another cell, the structure of which is still well preserved. This type of ingested nucleus, especially as found as an artifact in lupus erythematosus cell preparations.

Emperipolesis

  • Emperipolesis is the presence of an intact cell within the cytoplasm of another cell, an uncommon biological process, and can be physiological or pathological. Also called band cell
  • Seen with Rosai Dorfan disease, Hodgkin lymphoma, Myeloid neoplasms - AML, CML, MDS, MPD

[[Pasted image 20210718195837.png]]

Footnotes
1.
Graves disease is the most common cause of hyperthyroidism and often affects women. It is an autoimmune condition that is associated with circulating TSH receptor autoantibodies leading to overstimulation of the thyroid gland with excess thyroid hormone production.
2.
Myasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by generalized muscle weakness. The pathophysiology of MG involves autoantibodies directed against postsynaptic acetylcholine receptors (AchR), thereby impairing neuromuscular transmission.
3.
A function of FOXP3 is to suppress the function of NFAT and NFkappaB and this leads to suppression of expression of many genes including IL-2 and effector T-cell cytokines.