L-15 Immune system and related diseases

The Immune System and Selected Immune Related Diseases

• Disorders of the immune system include Hypersensitivity Reactions, Transplant Pathology, Autoimmune Diseases, Immunologic Deficiency Syndromes and Amyloidosis
• The Mechanisms of Injury include
  • Type l Hypersensitivity (Immediate or Anaphylactic)
  • Type ll (Antibody Mediated Cytotoxicity):
    • Complement Dependent Reactions
    • Antibody Dependent Cell Mediated Cytotoxicity
    • Antibody Mediated Cellular Dysfunction
  • Type III (Immune Complex Mediated)
  • Type IV (Cell Mediated)

Type I Hypersensitivity

• Type I Hypersensitivity also referred to as Immediate or Anaphylactic
• A rapidly developing immunologic reaction occurs within minutes after the combination of an antigen with antibody bound to mast cells or basophils
• This reaction occurs in previously sensitized individuals to the antigen, and is Hyper-responsive

Systemic Reactions

• Follows an intravenous injection of an antigen
• The host is previously sensitized
• Shock is produced and/or is fatal within minutes;
• Systemic Anaphylaxis can elicit:
  • Vascular shock (Hypovolemic shock)
  • Edema
  • Difficulty in breathing
  • Reactions after administration of foreign proteins

Local Reactions

• Depends on the portal of entry of the allergen
• Determines local clinical manifestations such as:
  • Swelling (hives)
  • Nasal and conjunctival discharge (allergic rhinitis)
  • Bronchial asthma
  • Allergic gastroenteritis (food allergy)
• Local Immediate Hypersensitive Reactions can result from allergic Reactions to:
  • Pollen
  • Animal dander
  • House dust
  • Foods

Allergic Reactions Mediated by lgE

• Allergic reactions can manifest clinically as anaphylaxis:
  • Allergic asthma
  • Urticaria
  • Angioedema
  • Allergic rhinoconjunctivitis
  • Drug reactions
  • Atopic dermatitis
• Note: These reactions tend to be mediated by lgE

Systemic and Local Phases

• Reactions are either Systemic or Local
• Initial Phase (Location Dependent) entails:
  • Vasodilation
  • Vascular leakage
• Late phase includes: – Inflammatory cell infiltrate – Tissue destruction

Characteristics: Asthma

• Asthma can be:
  • Extrinsic
  • Intrinsic
• Bronchial Asthma involves:
  • IgE membrane binding
  • Mast cell activation and degranulation
  • Local affects
• 15 year old adolescent with a history of asthma seen in the ER with shortness of breath
• Started on beta adrenergic agonists by nebulizer and responded well
• Patient returns 7 hours later with severe dyspnea unresponsive to discharge medication
• Late phase reaction is most likely cause of this patients return to the ER.

Genetic Predispositions

• Atopy is the tendency to be prone to IgE-mediated allergic reactions
• Genetic predisposition to make IgE antibodies in response to allergen exposure
• Display Higher serum IgE levels and Increases in IL-4-producing T₁2 cells

Antibody Mediated Type II Hypersensitivity

• This type of hypersensitivity is Mediated by IgG or IgM. Mediated IgG or IgM targets antigens present on the surface of cells or other tissue components
• These antigens can be Endogenous or Exogenous
• The outcomes are
  • Complement Dependent Reactions resulting in Direct Lysis or Opsonization / Phagocytosis. -Antibody Dependent Cell Cytotoxicity resulting in Cell lysis such as Drug-induced hemolytic anemia. -Antibody Mediated Cellular Dysfunction resulting in Disruption of normal function.

Antibody Dependent Cell Cytotoxicity

• ADCC Characteristics:
  • Nonsensitized cells with Fc receptors
  • Ab Coating of target cell
  • Cell lysis without phagocytosis of:
    • Tumor cells
    • Parasites
• Involves Rh System & Transfusion Reaction

Antibody Mediated Cellular Dysfunction

• Type II hypersensitivity
• Characteristics:
  • Myasthenia Gravis (inhibitory)
  • Grave Disease (stimulatory)

Type III Hypersensitivity

• Antigen-antibody complex mediated tissue damage by complement activation
• Involves:
  • Ag-Ab complexes or Complex deposition in tissues resulting in Systemic Immune Complex Disease
  • Inflammatory response to complex deposits

Resulting Manifestations

• Glomerulonephritis (Kidney) can result in Proteinuria.
• Arthritis (Joints) result in Joint pain
• Ag-Ab complex deposition in postcapillary venules
• Vasculitis (Blood vessels-a common manifestation) which results for example in Urticaria.

Type IV Hypersensitivity

• Also called Cell Mediated Hypersensitivity
• Response to Intracellular microbes or Non-degradable antigens, or an allergen
• Is the immune response for contact dermatitis from poison ivy or nickel allergy.

Cellular Events In T Cell-mediated Hypersensitivity

• APC drives T cell differentiation
• Proliferation and Differentiation of CD4+ T Cells.
• APC drives for TH1 or TH17 cell differentiation where:
  • TH1 cells secrete cytokines (IFN-γ).
• Cell Mediated Responses of Differentiated Effector T Cells:
  • Macrophage enhanced killing
  • Inflammation is promoted by APCs
  • TH17 promote inflammation

Examples of Type IV

• Tuberculin Reaction
  • Intracutaneous injection of PPD into Exposed Patient
• Reaction is Reddening and induration at site 8 to 12 hours post-injection
• Morphology of reaction shows Perivascular "cuffing" of Mononuclear cells such as CD4+ T cells or Macrophages are seen

Transplant Pathology Immune Mechanisms

• Host vs Graft Disease
• Graft vs Host Disease that has Graft resident immune cells mount attack on organ

Host vs. Graft

• The Immune System of the Recipient recognizes graft as being foreign and will Attack against unrecognized antigens.

Patterns of Rejection Include

• Hyperacute-mediated by preformed antibodies specific for antigens on graft endothelial cells
• Acute Rejection is Mediated by T cells and antibodies activated by alloantigens in the graft -Acute cellular rejection -Acute humoral rejection
• Acute antibody-mediated (vascular, or humoral) rejection
• Chronic Rejection is An indolent form of graft damage that occurs over months or years, leading to progressive loss of graft function.

Hyperacute Rejection

• Preformed antibodies may be natural IgM antibodies specific for blood group antigens
• Preformed antibodies may be specific for allogeneic MHC molecules that were induced by:
  • Prior exposure of the organ recipient to allogeneic cells such as:
    • Blood transfusions
    • Pregnancy
    • Transplantation of another organ-
• Clinically Hyperacute Rejection is characterized by Cyanotic and Mottled tissues
  • Fibrin-platelet thrombi
  • Neutrophils infiltrates / Thrombotic occlusions of Arterioles, Glomeruli & Peritubular capillaries
  • Fibrinoid necrosis

Acute Cellular Rejection

• Mediated by T cells and antibodies that are activated by alloantigens in the graft
• CD8+ CTLs may directly destroy graft cells
• CD4+ cells secrete cytokines and induce inflammation that damages the graft.

Acute Humoral Rejection

• Mediated by T cells and antibodies that are activated by alloantigens in the graft
• Antibodies bind to vascular endothelium
• activate complement via the classical pathway
• Resultant inflammation and endothelial damage causes graft failure

Chronic Rejection

• Occurs over months or years
• Manifests as interstitial fibrosis
• Gradual narrowing of graft blood vessels (graft arteriosclerosis)
• Mediators: T cells that react against graft alloantigens and secrete cytokines
• Cytokines stimulate the proliferation and activities of fibroblasts and vascular smooth muscle cells in the graft
• Alloantibodies also contribute
• Results Progressive renal failure is apparent with increased serum Creatinine
• Interstitial fibrosis, Tubular and glomerular atrophy and scarring
• Shrinkage of parenchyma and Vascular Changes
• Obliterative intimal fibrosis presents

Autoimmune Diseases

• Pathogenesis involves Inheritance of susceptibility genes, Breakdown of self-tolerance & Environmental triggers, tissue dame and self reactive lymphocytes

Immune Regulation Contains

• Self-tolerance through lack of responsiveness to an individual's own antigens
• Central Tolerance through Elimination utilizing immature self-reactive T / B-lymphocyte clones
• Peripheral Tolerance:
  • Mechanisms to silence autoreactive T / B cells in peripheral tissues through:
    • Anergy
    • Suppression
    • Apoptosis-Fas/FasL association

Mechanisms and Role of Infection in Autoimmunte Diseases

• Molecular Mimicry in Rheumatic Heart Disease or Antibodies production to bacterial M-proteins that cross-react with Human cardiac antigens like Myosin, Valvular endothelium and Laminin that results in Pancarditis and Valvulitis. SLE, Sjogren's Syndrome and Systemic Sclerosis (Scleroderma)

SLE - Systemic Lupus Erythematosus

• Pathogenesis: results from Failure of regulatory mechanisms that recognize self-antigens:
• Results in Antibody Mediated Injury Directed Against Heart, Kidney, Joints, Skin, Serosal membranes ,Virtually all organs.

Clinical Criteria

• 4 or > of 11 Criteria needed for Diagnosis and includes "SOAP BRAIN MD"
  • Serositis
  • Oral ulcers
  • Arthritis
  • Photosensitivity
  • Blood disorders
  • Renal Disorders proteinuria)
  • ANA positive
  • Immunologic disorders
  • Neurological disorders
  • Malar rash
  • Discoid rash
  • Lab includes 26 year-old woman with fever and rash on her face, ANA +,WBC , Hgb, PLT levels
  • Creatine Urinalysis, ESR and Complement
  • In Diagnosis note if there are Antibodies utilizing a Screening Ab or Antinuclear Antibodies with Specific testing used
  • DNA Anti-dsDNA & Anti-Sm

Lupus Cerebritis

• Obstruction to cerebral blood flow that is related to Neuropsychiatric manifestation

Sjogren Syndrome

• Immune mediated destruction of the lacrimal and salivary glands that is associated with Keratoconjunctivitis or Dry Eyes & Xerostomia or Dry Mouth known at Sicca Symptoms:
  • Keratoconjunctivitis (Dry Eyes)
  • Xerostomia (Dry Mouth)
• The Sjogren syndrome may either be a Primary Sjogren syndrome or a Secondary Sjogren syndrome: -Mikulicz Syndrome

Etiology and Pathology of Sjogren Syndrome

• An Antigen driven CD4+ T cell activation may result in Fibrosis of lacrimal and salivary glands with ANA positivity, or detection of ribonucleoprotein, a SS-A (Ro) and SS-B (La) Antigen

Evaluation of Sjogren Syndrome

Salivary Gland Enlargement with Lymphocytic Infiltrate, Plasma Cell Infiltrate, Ductal Hyperplasia involves Schirmer Test & Xerostomia Women between 50-60 y/o may also present with Raynaud phenomenon, Gl disease or Pulmonary disease and a Risk of malignancy

Systemic Sclerosis

• Divided into Scleroderma, Diffuse cutaneous systemic sclerosis, Early widespread skin involvement with Rapid progression or Early visceral involvement or Limited cutaneous systemic sclerosis where it Confined to fingers, forearms, face.
• Visceral involvement occurs late
• Cause Unknown through Oligoclonal CD4+ T cell, Ag driven expansion, Growth factor accumulation,Fibroblast stimulation & Microvascular Disease Lung biopsy demonstrates severe interstitial fibrosis and medial fibrosis and pulmonary hypertension
• Patients exhibit Nodules or Blue fingertips, Food stuck in throat or Esophagus, Stiffness and tightness of fingers or Small visible dilated blood vessels
• Associated with CREST Syndrome

Clinically

• Scleroderma (Systemic Sclerosis) may present with:
  • Sclerodactyly
  • Digital ulceration
  • Loss of skin creases & Joint contractures
  • Sparse hair with Tightening and Beaklike facies
  • There are Laboratory differences in the evaluation of Diffuse Scleroderma and Limited Systemic Sclerosis

Primary Immunodeficiency States

• Linked Agammaglobulinemia
• Thymic Hypoplasia
• Common Variable Immunodeficiency, Isolated lgA Deficiency and Severe Combined Immunodeficiency (SCID) & Wiskott-Aldrich Syndrome
• In X-linked Agammaglobulinemia is from Mutation of Bruton tyrosine kinase Btk that Ab deficient results in manifestations after 6 months.

DiGeorge Syndrome

• Thymic Hypoplasia (DiGeorge Syndrome), and the Thymus does not develop properly which results after Gene deletion at 22q11.
• There a resulting Loss of T cell immunity and patients may display susceptibility to fungal and viral infections

Severe Combined Immunodeficiency

• SCID is in autosomal form is related Adenodide Deaminase Toxicity to rapidly dividing cell

Wiskott-Aldrich Syndrome

• Immunodeficiency with Thrombocytopenia & Eczema from a Gene Mutation in an X-linked Recessive Disease that includes Thrombocytopenia, Eczema with Recurrent infection which results in Early death. Cytoskeleton dependent response

Acquired Immune Deficiency Syndrome

• Human Virus are CD4 cells that Decrease bone marrow
• Involves virus in cell decreasing protein reducing host protein disrupting assembly that ends in damage/cellular lysis.

Acquired Immune Deficiency Syndrome

• Sexual Transmission of virus predominantly mode of transmission, involving semen as other STDs .
• Can occur from IV Drug but blood products is rare to cause since 1985.

HIv 1

• In Utero is transplacental which has treatment protocols for both.

HIV

• Consists of HIV-1, HIV-2 and has gp120 gp 41, p24 capsid, the Reverse & the Transcriptase & RNA within.

Infection of HIV

• R5 stains: use CCR5 for preferntial infection of monocytes/macrophages and it is dominant virus in 90% acutely infected individuals.
• X4 Strains: us CXCR4 being T-trophic
• R5X4 – Dual-tropic T cell loss is from apoptosis Three Phases of Infection includes Acute, Chronic & Crisis

Acute and Chronic Infection from HIV

• The acute phase is when HIV develops rapidly and there is Flu-like symptoms, and the immune response is developing.
• The Chronic period then results from the Acute period to include opportunistic issues but T cell counts drop

Advanced Disease is Systemic and Immune Related

• Include the following Opportunistic infections or secondary neoplasms also AIDS Dementia, fatigue, weight loss, diarrhea and fevers.
• Targets the Immune system & CNS includes Macrophages can release more to the point of not functioning

Diagnosis of AIDS

• Elisa/ Western - Detects antibody antigen with 2 bands and protein electrophoresis is involved with p24/41 and gp 120/160 & Western Blot at least 2 bands on 2 test for antibodies is used.

Amyloidosis

• Substance that has Proteinaceous deposits intra extracellularly in various tissues.

Fibril Composition

• The Amyloid is Nonbranching fibris. They have 7.5 to 10 nm diameter and display Crossed beta pleated sheet conformation.
• Can be Congo that deposits on and turns the molecules red.

The General Types of Amyloid

• Systemic Amyloidosis where you see Immunocyte dyscrasias with amyloidosis is that of Multiple myeloma and other monoclonal plasma, and Systemic amyloidosis see Heart deposition / dysfunction due to Mutated transthyretin protein. Localized, Endocrine form of amyloidosis or Type 2 DM displays Islet deposits of amyloid

Amyloids

• Clinical Nature of Amyloid includes AL Amyloid light chain Complete immunoglobulin light chains Amino-terminal fragments with light chains Secreted by monoclonal population of cells • Amyloid fibril derived from non-lg protein made by the liver • Cleavage product Transmembrane protein and the wall with vessels

Pathogenisis of Amyloid

The abnormal folding in protein can involve infections & genetics. and gene transcription issues can cause deposits in extracellularity with normal function interuption.

Amyloidosis, such involvements are primarily caused by: heart, renal,cardiac The diagnosis depends on amyloid deposits in tissues, a process can be diagnosis based on the staining test (specific. Cardiac bx test if heart problems with it will diagnose the problems 3. CC: 86 yo man with feelings of butterflies in chest". What will you: What do you feel dizziness with butterflies.

Autoimmunity Cases:

• Normally, potentially pathologic autoimmune reactions are avoided because of the immunologic tolerance mechanisms of clonal deletion and clonal anergy
• Which can cause this? : A regulatory T-cell defect
• Eye trauma can cause systemic release of melanin-containing uveal cells, which triggers sympathetic ophthalmia
• Which best describes this mechanism for autoimmune disorders?
  • Alteration of body proteins

Autoimmunity disorders

• In autoimmune disorders, the immune system produces antibodies to an endogenous antigen
• Which of following conditions is from chemical alteration of autoantigens?
  • Drug-induced hemolytic anemia