Type I Hypersensitivity Information:

• Mediators:

  • Histamine

  • Eosinophil chemotactic factor of anaphylaxis (ECF-A)

  • Heparin

  • Neutrophil chemotactic factors

  • Various proteases

  • Prostaglandin

  • Leukotrienes

  • Platelet activating factor (PAF)

  • IL-4

  • Other cytokines

• Immune Mechanism

  • Sensitization

    • Initial exposure

    • IgE synthesized

    • Binds to mast cells and basophils in smooth muscle, blood vessels, and mucosal linings via FceR1 receptors

  • Activation

    • Subsequent exposure

    • Crosslinking of IgE on mast cells and basophils

    • Degranulation releases mediators

• Reaction time

  • 2-30 minutes

• Examples:

  • Anaphylaxis

Type II Hypersensitivity Information:

• Mediators:

  • Cell bound antigen

  • IgG and IgM

• Immune Mechanism:

  • Ab coats cell surface

  • C’ activated

  • cell lysis

  • opsonization

  • phagocytosis

  • Results in cell damage, destruction and dysfunction

• Examples:

  • Blood transfusion reaction

  • Goodpasture’s

  • Graves disease

Type III Hypersensitivity Information:

• Mediators:

  • Immune complexes

• Immune mechanism:

  • Ab combines with soluble Ag —> immune complex formation

    • Deposit in tissue (joints, lungs, skin, kidneys)

    • Activate C’

    • Influx of inflammatory cells

    • Prolongs total inflammatory response

• Examples:

  • Arthus reaction

  • Rheumatoid arthritis

  • Lupus

Type IV Hypersensitivity Information:

• Mediators

  • Th1 and Cytotoxic T-cells

• Mechanism:

  • Antigen forms complex with skin proteins

  • APC presents Ag to Th1

  • Activated Th1 cells

    • Release cytokines

    • Recruit neutrophils

    • Activate macrophages

    • Activate cytotoxic T cells

  • Results in tissue damage

• Reaction time:

  • Sensitization phase — 1-2 weeks after exposure

  • Subsequent exposure — 48-72 hours after exposure

• Examples:

  • Contact dermatitis

  • Hypersensitivity pneumonitis

  • TB skin testing

Autoimmune disease

• Loss of tolerance

• Women> men

• African ethnicity > European ethnicity

• Many triggers: hormonal, environmental, infectious

• Many systemic manifestations

• Organ specific disorders often have/ develop systemic problems

• Various lab tests for diagnosis

• ANA screening for various autoAb

Autoimmune disorders

• Grave’s disease

  • Overview:

    • Excess thyroid hormones causing hyperthyroidism

    • Thyrotoxicosis

    • Women in 50s and 60s

    • B-cells produce TRAbs, anti-Tg, anti-TPO

  • Symptoms:

    • Nervousness,

    • agitated

    • Insomnia

    • Depression

    • Weightloss

    • Rapid Heart beat

    • Firm goiter

    • Exophthalmos

  • Laboratory results for Grave’s Disease

    • Low TSH

    • High FT4

• Hashimoto’s thyroiditis

  • Overview

    • Most common autoimmune dz

    • Mostly middle-aged women

    • Immune destruction of thyroid gland produces hypothyroidism

      • Pathology mediated by activated CD8+ cells

      • Anti-Tg

        and anti-TPO can fix
        C’Further tissue damage to thyroid gland

    • Symptoms of Hashimoto’s Thyroiditis

      • Fatigue

      • Dry skin

      • Puffy face

      • Swollen eyelids

      • Weight gain

      • Brittle hair

      • Rubbery goiter

    • Lab results for Hashimoto’s Thyroiditis

      • Normal or High TSH

      • Low free T4

  • Type 1 Diabetes Mellitus (T1DM)

    • Overview:

      • Endocrine disorder

      • Destruction of beta cells

      • Insulin deficiency

      • Hyperglycemia

      • Long term effects:

        • CVD

        • Kidney damage

        • Nerve damage

    • Lab results:

      • High glucose levels

      • Fasting greater than or equal to 126 mg/dl

      • Oral GTT > 200 mg/dL

      • Elevated HbA1c > or equal to 6.5%

• Celiac Disease

  • Affects small intestine and triggered by gluten

  • Symptoms: diarrhea, abdominal pain

  • Treatment: follow a gluten free diet

  • HLA-DQ2 or DQ8- positive individuals

  • AutoAb formed to:

    • Gliadin (component of gluten)

    • DGPs ( gliadin peptides)

    • Endomysium (intestinal tissue)

• Multiple Sclerosis (MS)

  • Inflammation and destruction of axons in the central nervous system

  • Plaques form in the brain and spinal cord

  • IgG against myelin basic protein

    • Stimulates macrophages, microglial cells

    • Th1 cytokines released

    • CTLs recruited

  • Destruction of myelin sheath of axons

    • Demyelination

    • Inflammation and injury

    • Neurodegeneration

  • Young-middle aged adults (20-50 yrs old)

  • Women 2x more than men

  • Symptoms:

    • Visual disturbances

    • Weakness in limbs

    • Dizziness

    • Sensory abnormalities

    • Diminished dexterity

    • Facial palsy

  • Lab results

    • Lesions seen on MRI

    • Increased IgG in CSF

    • Increased IgG index

    • Oligoclonal bands on protein electrophoresis of CSF

• Myasthenia Gravis

  • Affects neuromuscular junction

  • Weak skeletal muscles

  • Antibodies to acetylchloline receptor (ACHR)

    • Block binding of ACH to its receptor

    • Blocks transmission of nerve impulses that activate muscles

    • Activates C’

    • Type II hypersensitivity

  • Symptoms of Myasthenia Gravis

    • Ptosis (eyelid droop)

    • Double vision

    • Corners of mouth droop

    • Upper body weakness

    • Difficulty speaking

    • Difficulty swallowing

• Goodpasture’s syndrome

  • Affects men in 30s

  • Affects men and women in 60s-70s

  • Strong genetic association with HLA-DR

  • autoAb reacts with collagen in glomerular basement of kidneys and alveolar basement of lungs

    • Activates C’

    • Attracts neutrophils

    • Injury/ destruction of membranes

    • Type II hypersensitivity

• Sjogren’s Syndrome

  • Immune cells damage the glands that make tears and saliva

  • Secondary form in people with SLE and RA

  • Patients present with dry eyes, dry mouth, tooth decay

  • AutoAb (Sjogren’s Syndrome)

    • anti-SSA

      • Anti-Sjogren’s-Syndrome-related antigen A

      • anti-Ro

    • anti-SSB

      • Anti-Sjogren’s Syndrome-related antigen B

      • anti-LA

  • ANA pattern: fine speckled

  • Present in 70% of Sjogren’s patients

  • anti-SSA/Ro and anti-SSB/LA

    • Present in 24-60% of lupus patients

    • Present in 70% of Sjogren’s patients

    • Associated with extreme sun sensitivity and cutaneous SLE

    • Can cross the placenta

    • Will cause neonatal lupus

      • Rash and congenital heart defects

• Scleroderma

  • Inflammation and pain of the skin, muscles, joints, and fibrous tissues

  • Produce too much collagen

  • CREST symptoms

    • Calcinosis

    • Raynaud’s phenomenon

    • Esophageal dysfunction

    • Sclerodactyly

    • Telangiectasia

  • ANAs:

    • Anti-SCL-70

    • Anti-centromere

• Ankylosing Spondylitis

  • Rheumatic inflammation of spine and sacroiliac joints

  • Common genetic marker found is HLA-B27

  • Elevated ESR

  • Anemia

  • MAINLY AFFECTS YOUNG MEN

• Systemic Lupus Erythematosus (SLE)

  • Overview:

    • Chronic systemic inflammatory disease

    • Multiple organ systems

    • Targeted Ag are parts of the cell nucleus

    • AutoAb develop

      • Anti-dsDNA

      • Other nuclear components

      • Lymphocytes

      • RBCs

      • Platelets

  • SLE immunopathology

    • Dysfunction of apoptosis

    • Dysfunction in clearing activity

    • Uncontrolled autoreactivity of T-cells

    • Polyclonal activation of B-cells

    • Many immune complexes form

    • C’ activation — Tissue damage

    • Complex deposition in tissues

  • Clinical Symptoms of SLE

    • Age of onset 20-40 yrs

    • Women> men

    • African > European

    • Joint involvement

    • Skin rashes (80%)

    • Renal involvement

    • Cardiac involvement

    • Cytopenias

• Drug Induced Lupus

  • Overview:

    • Different from chronic lupud

    • Symptoms disappear when drug is stopped

    • Mild symptoms:

      1. Fever

      2. Rashes

      3. Arthritis

    • Kidneys rarely involved

• Neonatal lupus

  • Maternal autoAb crosses placenta

  • Babies born with skin rash and possible congenital heart block

  • Anti-SSA/Ro and anti-SSB/La

• Rheumatoid Arthritis (RA)

  • Overview:

    • Chronic erosive arthritis of peripheral joints

    • Progress to joint deformity and disability

    • About 25% of patients have osteoporosis

    • Some patients also develop:

      • Subcutaneous nodules

      • Pericarditis

      • Interstitial lung disease Vasculitis

  • Immunopathology of RA

    • AutoAb combine with self-Ag to form immune complex

    • C’ activated

    • Immune complex deposition (type III hypersensitivity)

    • Inflammation destroys the bone and cartilage

    • Overly active osteoclasts absorb the bone

    • TNF-a plays a key role in the process

    • Commonly used medications: methotrexate, mAb to TNF-a

  • RA autoantibodies

    • ANAs (speckled) ~ 40% of patients

    • Rheumatoid factor (FR)

      • Class of IgM directed to IgG

      • IgM AutoAb reacts with Fc portion of IgG

      • Found in ~80% of patients with RA

      • Not specific for RA

        • Found in other autoimmune disorders and some chronic disease states

        • Can cause interference in some IA

    • Anti-CCP

      • AutoAb directed against cyclic citrullinated peptide (amino acid)

      • Performed by ELISA

      • Highly specific for RA

      • Not detected in SLE

      • Can differentiate RA from SLE

• Granulomatosis with Polyangiitis (Wegner’s)

  • Overview:

    • Inflammation of small to medium sized blood vessels in respiratory tract

    • Neutrophil activation results in damage to vascular endothelium and a Th1 response

      • Chronic upper and lower respiratory infections/symptoms

      • Sinusitis, rhinitis

      • Nasal and oral ulcers

      • Gingivitis

    • Progresses to more systemic disease involving other organs (e.g. kidneys, joints, skin)

  • Anti-Neutrophil Cytoplasmic Antibodies (ANCA)

    • Most patients have antibodies to neutrophil cytoplasmic antigen

      • Proteinase 3 (PR3)

      • Myeloperoxidase (MPO)

    • Detected by IIF on ethanol-fixed neutrophils, ELISA, or CLIA

      • 2 patterns: c-ANCA, and p-ANCA

        • c-ANCA —

          • Ab to PR3

          • Diffuse, granular staining in cytoplasm between nuclear lobes

          • SPECIFIC TO WEGNER’S

        • p-ANCA —

          • Ab to MPO

          • Staining surrounds nuclear lobes, blending together

          • Seen in ulcerative colitis, vasculitis, and rheumatoid arthritis

Immunoproliferative disorders

• Multiple Myeloma: monoclonal gammopathy (IgG), crab features, bone lesions

• Waldenstrom’s macroglobinemia: monoclonal gammopathy (IgM), similar to MM but no bone lesions

Immunodeficiency disorders

• Transient hypogammaglobulinemia

  • Maternal Ig decline at 5-6 months

  • IgG most affected

  • With or without depression of IgA and IgM

  • Normal levels of B-cells (CD19)

  • Delayed maturation of Th cells

  • Mostly males affected

  • Pyogenic URI and skin infections

  • Ig levels normalize spontaneously at 9-15 months

• Bruton’s agammaglobulinemia

  • Presents in infancy

  • Affects males exclusively

  • Btk enzyme enzyme required for Ig gene rearrangement in pre-B stage

    • B cells halted at this stage

    • No B cells progress past this stage

  • NO CD19 B-cells in circulation

  • No plasma cells in lymphoid tissue

  • No IG of all classes= Agammaglobulinemia

  • T-cells are normal and abundant

  • Treated with gamma globulin injections

• Selective IgA deficiency

  • Most common PID ~1 in 500 people

  • Impaired differentiation to IgA - producing plasma cells

  • Patients may be asymptomatic or more prone to infections, allergies, and autoimmunity

  • 20% also have IgG2 deficiency

  • 30-40% will produce IgE anti-IgA

  • Cannot treat with gamma globulin injections

• IgG subclass deficiency

  • IgG heavy chain gene mutations

  • 70% IgG1, 20% IgG2, 6% IgG3, 4% IgG4

    • Low IgG1 or IgG3

      • No response to pathogen protein Ag

      • EX: bacterial toxins

    • Low IgG2 or IgG4

      • No response to pathogen polysaccharide Ag

      • EX: encapsulated bacteria

• SCID

  • Related diseases that affect T- and B- cells

  • X-linked recessive

  • Mutation in IL2RG gene — Abnormal signaling, halts maturation

  • Mutation in JAK3 gene — No Ab production or lymph proliferation

  • Adenosine deaminase deficiency — Toxic purine metabolites, dec lymphocytes

  • Most serious of all PID

  • Presents in early infancy

  • Any type of infection

  • Oral yeast infections

  • Pneumonia

  • Diarrhea

  • BM transplant, gene therapy

• PNP

  • Rare; presents in infancy

  • Enzyme needed to metabolize purines

  • dec T cells because of purine buildup

  • Chronic infections

  • failure to thrive

  • Some neurological issues

  • Can be confused with neonatal HIV

• Wiscott Aldrich

  • Rare, X-linked recessive PID

  • Characterized by

    • Immunodeficiency

    • Eczema

    • Thrombocytopenia

  • Lethal for children

    • Infection, hemorrhage, malignancy

  • Treat with BM transplant or cord blood stem cells

  • Normal B-cells

  • T-cells affected

  • Short platelet half life

  • Defect in CD43 (WAS gene)

  • Lab results

    • Low IgM

      • ABO blood typing affected

    • Normal IgA and IgG

    • High IgE

    • Low platelet count

    • Small platelet size

    • Prolonged bleeding times

• DiGeorge Syndrome

  • Developmental abnormality in 3rd and 4th pharyngeal pouches in embryo

  • Most patients have deletion in Chromosome 22

  • Thymus is not developed

  • Low or absent T-cells

  • Humoral is NOT affected

  • Treat with Thymus transplants

  • Underdevelopment / absence of Thymus

  • Decreased T cells

  • Hypoparathyroidism

  • Hypocalcemia

  • Tetany — involuntary muscle contractions that are seizure like

  • Cardiac abnormalities

  • Mental developmental delay

  • Abnormal facial features

  • Severe, recurrent viral infections

  • Severe, recurrent fungal infections

• Ataxia-telangiectasia

  • Rare autosomal-recessive syndrome

  • Neurodegenerative disease

    • Ataxia — involuntary muscle movements

    • Telangiectasias — capillary swelling and red blotches on skin and/or eyes

  • Abnormal genes

  • Errors in gene rearrangement

  • Combined defect to humoral and cellular Immune system

  • Poor Ab response

  • Dec T cells

  • Low/ no IgG2, IgA, IgE

  • Improper DNA damage repair

  • Build up of mutations

• Phagocyte enzyme deficiencies

  • Chronic granulomatous disease (CGD)

  • Myeloperoxidase (MPO) deficiency

  • X-linked recessive or autosomal recessive

  • Often fatal to children

  • Neutrophils unable to generate oxidative burst

    • Defect in NADPH oxidase system

    • Decreased killing of catalase (+) organisms

    • Recurrent infections, pneumonia, osteomyelitis

    • Impairs wound healing, abscess

• C’ Deficiencies

  • Most are inherited as autosomal recessive

  • Early C’ components

    • Associated with a lupus-like syndrome

    • C2 deficiency most common

    • C3 deficiency associated with recurrent infections with encapsulated bacteria

  • Late C’ components

    • Associated with Neisseria meningitides infections

  • Regulatory deficiencies

    • C1INH, DAF

Transplant Immunology

• Classification of Grafts

  • Autograft — Tissue transfer in the same individual

    • Example: saphenous vein in cardiac bypass

  • Syngeneic (Iso) graft — Transfer of cells or tissues to a genetically identical individual

    • Example: transplant between identical twins

  • Allograft — Graft between genetically nonidentical individuals of the same species

    • Example: graft from an unrelated cadaver donor

  • Xenograft — Transplant between members of a different species

    • Example: transplant of pig valve into human heart

• Types of rejection

  • Hyperacute:

    • Occurs minutes to hours after the transplant

    • Performed antibodies to ABO, HLA, and endothelial antigens bind to vascular endothelium and active C’ and clotting factors

  • Accelerated:

    • Occurs few days after the transplant

    • Mechanisms same as hyperacute

  • Acute:

    • Occurs days to months after the transplant

    • Cytokine production by Th induced delayed-type hypersensitivity (DTH)

    • CD8+ T cells mediate cytotoxicity

    • Antibodies fix C’ and induce inflammation

  • Chronic:

    • Rejection 1 year or more after transplant

    • Memory T-cells mediate DTH

• Direct v Indirect recognition

  • Direct:

    • Cytotoxic T-cells from the recipient bind directly to foreign HLA antigens on the cells of the allograft and release cytotoxic factors

  • Indirect:

    • Host APCs present foreign MHC antigens on graft cells to recipient Th cells

    • May play important role in alloAb production and chronic rejection

• HLA genes — MHC class

  • MHC antigens

    • Closely linked genes on chromosome 6

    • Highly polymorphic and induce strong graft rejection

    • Class I proteins

      • HLA-A, HLA-B, HLA-C

      • Expressed on all nucleated cells

    • Class II proteins

      • HLA-D (DR,DQ,DP)

      • Expressed on antigen presenting cells

    • The HLA system is the most polymorphic genetic system in humans

    • Grants survival from pathogens encountered

    • Restricts ability to transplant foreign cells and tissue

    • HLA proteins are highly immunogenic

      • Thousands of HLA alleles = many HLA genes = numerous combos

  • Class I MHC molecule

    • Heterodimer consisting of polymorphic a- chain non-covalently bonded to B-2 microglobulin

    • Extracellular region of a-chain is divided into 3 domains

      • a1, a2, a3

    • Coded for by HLA-A, B, C

    • All nucleated cells

    • Presents intracellular antigen to CD8+ T cells

  • Class I MHC graft rejection

    • DIRECT allorecognition

    • MHC class I expressed on/shed by donor graft

    • CD8+ T-cells activate and cause cytotoxic cell lysis

    • Cells on donor graft are destroyed

    • Graft tissue does not survive in recipient

  • Class II MHC molecule

    • Heterodimer consisting of polymorphic a-chain bonded to polymorphic b-chain

    • a-chain and b-chain have two domains each

      • a1a2 B1B2

    • Coded for by HLA-D locus

    • 3 subregions: DR, DQ, DP

    • Antigen presenting cells

    • Presents extracellular antigen to CD4+ T-cells

  • Class II MHC graft rejection

    • Indirect recognition

    • Peptides from donor graft are taken in by recipient APC

    • APC present peptides by MHC class II to CD4+ Th cells

      • Th1 cells= cellular Immune response

      • Th2 cells = humoral immune response

      • Donor cells are destroyed

• ABO blood type for transplant

  • The only blood group system that affects solid organ transplant

  • Major contingency for blood and blood product trnasfusion (also considered a transplant)

  • Antibodies strongly bind to RBCs and vascular endothelium, activating C’ cascade = rapid rejection = HYPERACUTE REJECTION

  • Recipient-donor pairs must be ABO-identical or compatible

• Other Histocompatibility systems

  • Minor Histocompatibility antigens (mHAs)

    • non-HLA proteins

    • Also demonstrate amino acid variation

    • Recorded tissue rejection in MHC-identical transplants

    • Recorded GVHD in HLA-identical sibling stem cell transplant

    • CD4 or CD8 T-cells recognize variant protein and mediate Immune Response

    • Similar to reaction toward microbial antigen

  • MHC Class I- Related Chain A (MICA)

    • Polymorphic > 50 allelic variants

    • Antigens expressed on endothelial cells, keratinocytes, fibroblasts, epithelial cells, dendritic cells, and monocytes

    • Antigens are NOT expressed on T-cells or B-cells

    • Anti-MICA antibodies found in 11% of kidney transplant recipients

      • Rejection and decreased graft survival

• GVHD

  • Lymphoid cells in graft mount immune response against recipient’s histocompatibility antigens

  • Caused by immune response of T-cells of donor HSC, lung, or liver transplant

  • Involves massive cytokine release inflammation, and destruction of various tissues (GI tract, skin)

  • Occurs 100 days or more after a transplant