Immunology - E4 Flashcards
Classical Complement System
- series of proteins that mediates host defense against various extracellular pathogens, especially bacteria.
- activated by Ag-Ab Complexes (both IgG and IgM)
- C1q, C1r and C1s bind to the complement binding site on the Fc portion of the antibody molecule (complex= Activated C1)
- Activated C1 splits C4 into C4a and C4b
- C4b sticks to activated C1 (complex= C14b)
- C14b splits C2 –> C2a and C2b (complex=c14b2b)
- C14b2b splits C3 –> C3a and C3b (complex=C14b2b3b)
- C14b2b3b splits C5 –> C5a and C5b
- C6, C7, C8 and C9 bind to C5b –> Membrane Attack Complex
Activated C1
Complex formed when C1q, C1r and C1s bind to the complement binding site on the Fc portion of the antibody molecule
C14b
C4b sticks to the activated C1 and this complex is called C14b
After C14b is formed
C14b splits C2 –> C2a and C2b (complex= C14b2b)
C14b2b splits C3 –> C3a and C3b (complex= C14b2b3b)
The complex of C14b2b3b splits C5 –> C5a and C5b
Membrane Attack Complex (MAC)
C6, C7, C8 and C9 attach to activated C5 –> MAT
- porates cell membranes causing osmotic disruption and lysis
Opsonization
Macrophages and neutrophils express a cell-surface receptor, called CRI, which binds to C3b
Microorganisms coated with C3b –> brought into contact with these phagocytic cells where they will be readily phagocytosed.
C3a and C5a functions
- Chemotaxis (attack phagocytes to site of antigen)
- Anaphylatoxin production (degranulate mast cells and basophils –> release histamine and other vasoactive substances that increase capillary permeability, inflammatory response)
“anaphylatoxins”
C1-inhibitor (C1-INH)
Inhibits the first step in the activation of the classical complement pathway
Alternative Complement Pathway
Activated by bacterial or viral products e.g. Lipopolysaccaride (LPS)
Occurs in the absence of specific antibody (thus, and effector arm of the innate immune system)
Proteins of the Alternative Complement Pathway
- C3b (generated from the natural breakdown of C3)
- Factor B
- Factor D
- Properdin
- ^ Together –> generate C3bBbP that splits C3 –> C3a and C3b and continues the complement cascade
Inhibitors of alternative complement pathway
Factor H and Factor I are inhibitors of the alternative pathway and regulate the activation of the system
Lectin pathway
Initiated when mannan-binding lectin binds to carbohydrates on the surface of microbes
Important proteins: MBL (Mannose binding lectin)
MASP 1
MASP 2
Absence of C1q, C2 or C4
Associated with SLE (systemic Lupus Erythematosus) – no recurrent infections, you have other pathways. But have a very high incidence of lupus
Absence of C3
Severe recurrent bacterial infections, no complement system
Absence of C5
Bacterial infections (have c3b and c3a, so not as bad)
Absence of C6, C7, or C8
Overwhelming Neisserial infections (N.meningitidis and N.gonorrhea) These ppl are fine until neisserial infection arises
Absence of alternative pathway components
Recurrent bacterial infections
Absence of Lectin pathway proteins
infection in childhood, overcome later in life by Ab/T-cell repertoire
C1-INH Deficiency
Hereditary angioedema
- Uncontrolled C2/C4 cleavage causing localized edema (not itchy, like hypersensitivity), causing increased kinin production (vasodilation).
Hereditary angioedema
- Rare AD disorder via inherited deficiency or dysfunction of the C1 inhibitor
- recurrent episodes of angioedema w/o urticaria or pruritus (affects the skin, mucosal tissues, upper respiratory and gastrointestinal tracts)
- swelling is self-limited, laryngeal involvement may cause fatal asphyxiation
C8 and C9 important functions
Lysis of organisms coated with specific antibody
CRI receptor
On macrophages/neutrophils, recognizes C3b for opsonization
T-cell regulation via CTLA-4
CTLA-4 is made which competes with CD28 (on T-cell) for B7 (on APC)
Deficiency –> autoimmune disease
T-cell regulation via PD-1
Programmed death 1 (PD-1) –> inhibitory receptor on cytotoxic T-cells, interacts with PD-L1 (on tumor cells ) and PD-L2 found on dendritic cells and macrophages –> inhibiting immune responses.
Pembrolizumab and nivolumab –> anti-PD-1 checkpoint inhibitors
T-cell regulation via activation induced cell death
Activated T-cells develop FasL that reacts with Fas normally ALSO present on T cells –> apoptosis of that cell.
T-cells are turned on (making cytokines, killing etc.) then develop fasL and kill themselves (immune response drops)
T-cell regulation via T-reg cells
T-reg cells make inhibitory Cytokines IL-10 and TGFβ which inhibit all T-cell functions.
Immunologic Tolerance
Lack of response to a specific antigen
Failure to induce specific immunity to that antigen
Self-Tolerance
- unresponsiveness to SELF antigens
- occurs in thymus (negative selection) –> “central tolerance”
Peripheral Tolerance Mechanisms
To deal with cells that escape central tolerance (self-tolerance)
- Clonal deletion: continuous exposure to self-Ag’s, –> continuous stimulation of T-cells –> apoptosis of autoreactive lymphocytes.
* occurs by the process of activation-induced cell death (Fas-FasL)
- only deleting the ONE clone - Clonal anergy: absence of co-stimulatory signals, especially B7-CD28)
- inactivation of T-cells which recognize antigen but are improperly activated due to a lack of adequate co-stimulator molecules on the APC.
-Autoreactive T-cells do not receive B7-CD28 interaction necessary, and are deleted as nonreactive.
lymphocytes)
Fetal tolerance
Tolerance is induced more readily in immature lymphocytes
White mouse with black skin transplanted in utero –> tolerant to black skin mouse organs
*Adult tolerance is difficult to produce, need to prevent co-stimulatory signaling (B7-CD28)
Autoimmune disease
Immunological response against self antigens due to loss of self-tolerance, may be due to …
- Failure of negative selection in the thymus
- Failure of immunological control mechanisms
Problem: Imbalance between immune activation and immune control
auto-immune hemolytic anemia
antibody against her red blood cells
How could exposure of hidden antigens give rise to autoimmunity?
Exp. sympathetic ophthalmia - Abs to lens proteins after eye damage
Any tissue antigens sequestered from the circulation (not seen by the developing immune system) will not induce self-tolerance. Exposure of mature T cells to such normally sequestered antigens at a later date could result in their activation.
How could polyclonal lymphocyte activation give rise to autoimmunity?
1) Viruses such as EBV stimulate B- cells non-specifically
2) Superantigens stimulate T-cells (non-specifically activating thousands of clones of T-cells)
(Attach to the OUTSIDE of the T-cell receptor and to OUTSIDE of the MHC Class II molecule causing T-cell activation)
Exp. Staphylococcal food poisoning, toxic shock syndrome
How could defective T-cell regulation give rise to autoimmunity?
- Defective Treg Cells (CD4+, CD25+) (Treg cells make inhibitory Cytokines IL-10 and TGFβ)
- Defective B7-CTLA-4 Interaction –> uncontrolled activation of T-cells
Genetic factors in autoimmunity
- Autoimmune disease more comm. in fam members. (certain in-bred strains of mice –> autoimmune disease (NZB/NZW))
- Increased incidence in twins
- Asocc of autoimmune diseases with MHC types (B27 - AS, DR3/DR4 - IDDM, DR4 - RA)
Molecular mimicry
Some microorganisms have antigenic determinants that are identical/similar to normal host cell components.
exp - Strep cell wall stimulates Ab response, autoAbs to heart valves develop in some individuals weeks after a strep infection –> Abs cross-react with heart tissue –> rheumatic fever
Microbial factors in autoimmunity
- molecular mimicry (rheumatic fever)
- abnormal activation of lymphoid cells (EBV)
- Microbes may damage tissue –> release of hidden antigens
- Microbes may function as adjuvants and stimulate immune responses
Adjuvant
Stimulate immune responses, make the response bigger.
Microbes may function as adjuvants: Tissue proteins taken up by antigen presenting cells do not produce an immune response because they fail to induce co-stimulatory proteins on the surface of the APC. When mixed with bacteria, however –> become immunogenic (bacteria induce the formation of MHC class II molecules and B7 on the surface of the APC.
Hormonal factors of autoimmune factors
Most autoimmune diseases are more common in females e.g. SLE 9:1, earlier (systemic lupus erythematosus)
Autoimmunity. Damage to the tissue may be mediated primarily by…
1) Antibodies e.g. autoimmune hemolytic anemia or myasthenia gravis,
2) T-cells e.g. Crohn’s disease, IDDM, psoriasis, multiple sclerosis,
3) Both humoral immunity and CMI e.g. Hashimoto’s thyroiditis or rheumatoid arthritis
In autoimmunity, Abs mediate damage to tissue in…
autoimmune hemolytic anemia or myasthenia gravis
In autoimmunity, T-cells mediate damage to tissue in…
Crohn’s disease, IDDM, psoriasis, multiple sclerosis,
In autoimmunity, humoral immunity and CMI mediate damage to tissue in…
Hashimoto’s thyroiditis or rheumatoid arthritis
Which autoimmune diseases are activated T-cells responsible for…
Insulin-dependent diabetes mellitus (IDDM) Rheumatoid arthritis Multiple sclerosis Crohn’s Disease Psoriasis Celiac Disease
^All primarily caused by T-cell attack. This may be followed by secondary auto-Ab production
Most common autoimmune diseases in the US
Graves' disease RA Hashimoto's thyroids Vitiligo IDDM
Autograft
One person to the same person
Syngraft
Person to a genetically identical recipient
Allograft
Person to a genetically different recipient
Exp. Mother to child (not HLA identical)
Xenograft
Graft to a different species
Hyperacute rejection
w/I minutes or hours. Preformed Abs in the recipient against graft endothelial cells. Abs may be present due to prev blood transfusions, pregnancies, prior transplants.
*not common bc recipients are tested for presence of pre-formed Abs against cells of donor
Acute rejection
completed w/i 10-14 days.
Due to cell mediated immunity (T-cells react against alloantigens in graft) but some injury is also Ab mediated
Chronic rejection
w/i months or years after the transplant. Due to Ab, T-cell and NK cell attack on the graft
Mechanisms of Acute Allograft Rejection
1) Direct contact between CD8+ cells and the graft (Perforin and Granzyme, Fas and FasL (on CD8))
2) Locally released cytokines and chemokines (IL-2 –> T-cell proliferation and differentiation of CD8+ cells, IFNγ –> activates macrophages, Interferon-gamma and TNF increase MHC expression on grafted cells)
3) Antibody against donor HLA
- Classical complement activation
- ADCC by NK cells
4) Direct NK cell attack
Stem cell transplantation
Get stem cells from peripheral blood (after treatment with colony stimulating factors) or from umbilical cord blood or from bone marrow.
Danger: competent T-cells from donor may be transplanted –> graft versus host disease
graft versus host disease (GVH)
rxn of donor T-cells against recipient MHC
1) graft must contain live T-cells (tissue from the bone marrow, thymus)
2) The recipient must be immunosuppressed
3) The donor and recipient must have different HLA types
- CD4+ T cells in the graft are activated by allogeneic molecules and produce a “cytokine storm” that recruits other T cells, macrophages and NK cells to create the severe inflammation characteristic of GVH
Differentiation between transplant rejection and GVD?
Transplant rejection: when kidney is transplanted, RECIPIENT’S T cells attack transplant
GVD: when bone marrow is transplanted, T cells in TRANSPLANT attack recipients tissues
Cyclosporine and FK506
(immunosuppressive drugs) block a T-cell phosphatase called calcineurin and inhibit cytokine production
Corticosteroids
(immunosuppressive drugs) inhibit cytokine production and are anti-inflammatory
Anti-CD3 monoclonal Ab
Immunosuppressive drug
Anti-IL-2 receptor Ab
Immunosuppressive drug (IL-2 –> T-cell proliferation and differentiation of CD8+ cells)
The problem with all forms of immunosuppressive therapy
normal immune responses against microorganisms are reduced –> increased incidence of infection
Intracellular bacteria e.g. Mycobacterium tuberculosis
Large viruses. Pox and Herpes viruses
Fungi e.g. Candida
Intracellular parasites e.g. Toxoplasma
Types of antigens on the surface of tumor cells
Virally controlled antigens
- Oncofetal antigens *as you mature, these disappear
1) alpha-fetoprotein - primary hepatocellular carcinoma
2) carcino-embryonic antigen (CEA) - colon carcinoma - Abnormal peptides made by tumor cells
- Mutant antigens (Her2/neu): found on breast cancers. If +, tx with herceptin (an anti-her2/neu)
- Tissue specific differentiation antigens (CD19, CD20 –> for B-cells, CD3, CD4 or CD8 –> for T-cells. PSA –> Prostate specific antigen)
Normal vs abnormal B cells
Normal B cells: CD19, CD20 lambda OR kappa.
Abnormal B cells: CD19, CD20 ALL lambda OR ALL kappa (not a mixture)
^ B-cell lymphoma
A malignancy of a single B-cell clone
Tumors may lose HLA Class I, how are they killed?
If tumors lose HLA Class I, they will not be killed by CD8+ cells but they will be killed by NK cells that recognize and are cytotoxic to HLA Class I negative cells
Natural Killer Cells (NK cells)
They are large granular lymphocytes (LGL’s)
- Destroy infected and malignant cells that have absent or defective Class I MHC (this may occur after viral infection or malignant transformation)
- Have Fc receptors that can bind to IgG –> ADCC
- activated by cytokines (IL-2, IL-12 and IFN gamma)
- produce a variety of cytokines
How NK cells kill cancer cells
Can attach directly if no MHC class I or through ADCC
Principal immune mechanism of killing tumor cells
Via cytotoxic CD8 cells (CTLs=cytotoxic T cells)
- granzyme and perforin
- expression of FasL on the CD8 cell combining with Fas on tumor cell –> apoptosis of tumor cell
(Killing also takes place by activated macrophages and by NK cells)
How do tumors escape?
1) They release immunosuppressive factors e.g. IL-10 and TGF-beta
2) They release factors that activate TREG cells (which make inhibitory cytokines)
3) They select antigen-negative variants
4) They upregulate the expression of immune checkpoint molecules such as PD-1 and PD ligand 1 (PD-L1)
Cancer Immunotherapy
- immunization against onogenic viruses (Hep B and HPV)
- stimulate innate response (Imiquimod (for superficial skin cancer) –> activates TLR7 –> inflammatory response. BCG (tb vaccine –> local inflammatory rxn in bladder wall –> tx for superficial bladder cancer)
- checkpoint inhibitors: block CTLA-4 or the PD-1/PDL-1 interaction to remove the “brakes” from cytotoxic T-cells
- CAR T-cells: engineered receptors, have specificity of a monoclonal Ab receptor grafted onto a T cell. Can remove patient’s T-cells and modify them so their receptors are specific to pt’s cancer cells.
- Monoclonal Abs
PD-1 and PD-L1 checkpoint inhibitor for cancer immunotherapy
PD-1 (on T-cell) and PD-L1 (on tumor)
- inhibit this rxn, takes breaks away of T cells
- -> risks of autoimmune disease
CAR T-cells
CAR-T-cells are engineered receptors, which have the specificity of a monoclonal Ab receptor grafted onto a T cell
Exp. cytotoxicity of CD19-specific CAR-expressing T Lymphocytes against B-cell lymphoma
MAb mediated killing
Complemented-mediated lysis and phagocytosis or can attach by macrophages or NKs
Immunotoxins
monoclonal Abs attached to toxins such as ricin or radioactive isotopes. These are delivered specifically to the malignant cells to initiate direct killing.
Rituximab
Monoclonal anti-tumor Ab
targets CD20 on B-cell lymphomas
Erbitux
Monoclonal anti-tumor Ab
targets growth factor receptors in colon cancer
Herceptin (anti Her2/Neu)
Monoclonal anti-tumor Ab
blocks growth factor signaling
*breast cancer
Bispecific T cell engagers
one arm binds to CD3 and the other to CEA
Exp. CEA CD3: designed to redirect T cells to tumor cells by simultaneously binding to CD3 found on T cells and CEA, a tumor surface antigen
Oncofetal antigens
(Type of antigens on the surface of tumor cells)
Oncofetal antigens *as you mature, these disappear
1) alpha-fetoprotein - primary hepatocellular carcinoma
2) carcino-embryonic antigen (CEA) - colon carcinoma
NK cell activation
Activated by IL-2, IL-12 (released by active APCs), IFN-gamma (released by NK cells causing macrophages to destroy phagocytosed microbes)
Reasons why individuals preferentially make IgE Abs
Unclear
- Genetic component
- Mode of administration of antigen. Skin or mucus membrane favors IgE
- Antigen-presenting cells preferentially activate TH2 cells resulting in B-cells producing IL-4 and IL-13
- ? Failure of control of TH2 cells
First/second exposure to pollen
1st exposure- IL-4 drives B cells to produce IgE in response to pollen antigens. –> Pollen-specific IgE binds to mast cell. Sits until second exposure
2nd exposure- Acute release if mast cell contents causes allergic rhinitis (hay fever)
Early phase mediators released by mast cells and basophils. Responsible for…
Responsible for the early symptoms of allergy (IgE controls release of these…)
Histamine (acute inflammatory sx: vasodilation, vascular permeability, etc.)
Proteases (tissue degradation and increased mucus production)
Leukotrienes (increase vascular permeability, mucus production, broncho constriction.)
Prostaglandins (constrict bronchial airways)
Platelet Activating Factor (PAF) - constricts bronchial airways, massive vasodilation –> anaphylactic shock
Chemotactic Factors for neutrophils and eosinophils
Late phase mediators released in the late phase of the acute allergic reaction
4-12 hrs after allergen exposure
Primarily cytokines released from eosinophils*, mast cells, macrophages and infiltrating T-cells.
The late phase can be controlled by corticosteroids that inhibit cytokine production.
- prominent in most allergic rxns, important cause of tissue injury. Activated by the cytokine IL-5 which is also produced by TH2 cells.
Examples of IgE mediated allergic reactions
- Allergic rhinitis (Hay fever) tree pollens, grass pollen, ragweed pollen, cat hair, dog hair, house dust mite, moulds etc.
- Bronchial asthma – bronchial constriction
- Acute drug reactions
- Food allergies
- Insect stings
Wasps
Hornets
Honey bees
Yellow jackets
Fire ants - Acute urticaria (Hives)
Diagnosis of acute allergic disease
- Skin prick tests (intradermal skin tests) - positive wheal and flare seen in 5-10 minutes
- Measure specific IgE antibodies (to e.g. cat hair, pollens, house dust mite etc.). ^RAST test
Tx of acute anaphylactic reactions
Epinephrine (Adrenaline) used to treat acute anaphylactic reactions
Tx of Type 1 allergic reactions
1) Remove the antigen e.g. house dust mite, moulds, cats, peanuts etc.
2) Treat symptomatically with antihistamines, anti-leukotrienes, corticosteroids
3) Omalizumab (a monoclonal antibody that inhibits IgE binding to mast cells, activation/release of mediators is limited)
4) Hyposensitization therapy (shots)
Hyposensitization (desensitization)
Multiple exposures to increasing concentrations of the antigen results in an increase of IgG antibodies.
(antigen exp.: Bee venom, cat hair antigen, grass pollen antigen)
Mechanism of hyposensitization (desensitization)
2 Possible reasons for the increase in IgG and the slow decrease in IgE:
1) Hyposensitization activates the Th1 cells
2) Hyposensitization activates TREG cells to inhibit the Th2 cells
Mast cells can be degranulated by mechanisms other than IgE…
- C5a and C3a (anaphylatoxins)
- Heat
- Cold
- Pressure e.g. dermatographism
- Exercise
- CNS effects via the vagus nerve
- Direct effect of drugs on mast cells
New drugs for asthma (FYI)
Benralizumab, an anti-interleukin (IL)-5 receptor monoclonal Ab that depletes blood and airway eosinophils and improves asthma symptoms
The IL-4 blocker Dupilumab also looks promising
Type ll Hypersensitivity (Cytotoxic reactions)
Abnormal Ab directed against a target organ causes destruction of the target cell by complement mediated lysis or by ADCC
Complement mediated lysis of rbc
(type II hypersensitivity)
antibody dependent cellular cytotoxicity (ADCC)
type II hypersensitivity
NK cells use perforin and granzyme kills target cell. Ab coated target cells destroyed.
Examples of Type II hypersensitivity
Autoimmune hemolytic anemia
Autoimmune thrombocytopenia
Goodpastures syndrome
Hyperacute graft rejection
Anti-receptor antibody diseases
- Myasthenia gravis
- Grave’s disease
Anti-receptor antibody diseases
Myasthenia gravis
Grave’s disease
Pt makes Ab against a receptor
Autoimmune hemolytic anemia
(anti-red cell antibodies)
AUTOIMMUNE THROBOCYTOPENIA
Abs against the platelets cause purpura
Goodpasture’s syndrome
anti-glomerular/alveolar basement membrane (glomerulonephritis and hemoptysis)
IgG is deposited on the basement membrane of the glomeruli and the lung alveoli
Hyperacute Graft Rejection
Pre-formed antibodies against antigens on transplanted tissue
• Activation of complement triggers the blood clotting cascade, leading to ischemia and loss of the graft within minutes to hours of transplantation
Myasthenia gravis
TII HS
Ab binds and inactivates Ach-Receptors at NMJ, preventing muscle contraction. BLOCKS receptor.
Grave’s Disease
TII HS
Ab binds and ACTIVATES TSH-receptor, causing
hypERthyroidism, increased thyroid hormone release.
No negative feedback mechanism of TSH inhibiting release from pituitary.
(High TH, low TSH)
Type lll Hypersensitivity (Immune-complex disease)
Ag-Ab complexes trapped in small vessels of body. Binding of complement triggers an inflammatory reaction damaging the vessel walls (vasculitis).
Process: 1. Excess immune-complexes (joints, skin, kidney).
- Release of anaphylatoxins (C3a + C5a) induce mast cell/basophil degranulation, and neutrophil infiltration.
- Neutrophils degranulate in vessel wall –> release lysosomal enzymes –> damage vessel wall (vasculitis)
*complement levels fall as complement is consumed
Systemic lupus erythematosus (SLE)
(Example of Systemic Immune complex disease) type III hypersensitivity reaction
Antigen is DNA and other nuclear components. Ab is anti-DNA and other antinuclear Abs (ANA). Complexes are trapped in the small vessels of the skin, kidney and joints (Butterfly rash)
Post-streptococcal glomerulonephritis
(Example of Systemic Immune complex disease) type III hypersensitivity reaction
Circulating anti-streptococcal Abs combine with streptococcal antigen. Complexes are trapped in the glomeruli.
Serum sickness
(Example of Systemic Immune complex disease) type III hypersensitivity reaction
Pts treated with serum from an animal such as a horse, will make anti-horse Abs
Drug reactions e.g.penicillin
(Example of Systemic Immune complex disease) type III hypersensitivity reaction
- Penicillin and other drugs can be responsible for Type l, Type ll, Type lll and Type lV hypersensitivity reactions.
Localised Immune complex disease (Arthus Reaction)
Arthus Reaction: Injected Ag into individual with pre-formed Ab –> localized neutrophil invasion and inflammation.
Exp. 1) Tetanus toxin given to a person who already has tetanus Abs
2) Hypersensitivity pneumonitis such as Farmer’s lung or Bird Fancier’s Disease
Farmer’s Lung (Hypersensitivity Pneumonitis)
Repeated mold inhalation (Actinomycete organisms in moldy hay) –> formation of IgG against mold –> further inflammation intrapulmonary Arthus-type reaction (Neutrophil invasion and complement activation) –> followed by delayed-type (Type IV) hypersensitivity (T-cell infiltration and cytokine release) reaction.
*mixture of type III and Type IV rxn
Systemic Immune complex diseases
Systemic lupus erythematosus (SLE)
Post-streptococcal glomerulonephritis
Serum sickness
Drug reactions e.g.penicillin
Type I Hypersensitivity:
Type II Hypersensitivity:
Type III Hypersensitivity:
Type IV Hypersensitivity:
Type I Hypersensitivity: immediate, IgE-mediated. Allergic response requiring previous exposure (exp. pollen)
Type II Hypersensitivity: IgG and IgM-mediated. Abnormal antibody causes autoimmune cytotoxicity. (exp. autoimmune Hemolytic Anemia)
Type III Hypersensitivity: IgG/IgM-mediated. (Xs ag-Immune-complexes stick in vessels of joints, skin, kidney. Release of C3a and C3b. Neutrophils release lysosomal enzymes –> vasculitis) (exp. lupus)
Type IV Hypersensitivity: (delayed) Requires memory T-cells from previous exposure (exp. contact dermatitis)
Delayed Hypersensitivity (Type IV)
The mechanisms of delayed hypersensitivity are the same as those for cell-mediated immunity (CD4 and CD8), but result is tissue damage.
(sensitization phase, effector phase) APCs present antigen on MHC II, releasing IL-12, and causing TH1 expansion –> IFN-gamma, IL2 –> CMI (macrophages, NK, CD8), and T cell proliferation
Activated memory T-cells also release cytokines IL-1, TNF –> endothelial adhesiveness, IL-8 –> leukocyte attractant or chemokine
Examples of Delayed Hypersensitivity
Contact dermatitis (Blistering skin lesions in response to antigens combining with skin proteins, causing sensitization)
Poison ivy
Cosmetics
Foreign chemicals
Latex – rubber
Metals e.g. nickel, zinc reacting with skin proteins
Tuberculin skin test
form of delayed hypersensitivity
Inject PPD (Purified Protein Derivative of M.tuberculosis) into the skin. Read after 48 hours.
Problem with this ^ Individuals born in other countries may have received BCG (tb vaccine), so have memory T-cells that can produce a + tuberculin skin test
Chronic infections that are forms of delayed hypersensitivity
forms of delayed hypersensitivity. Persistent antigen exposure may induce sensitization, causing chronic local delayed hypersensitivity reaction.
- Viral hepatitis (T cells killing your own liver)
- Chronic bacterial diseases e.g. Tuberculosis syphilis, leprosy
- Chronic fungal infections e.g. Candidiasis
- Parasitic diseases e.g. Leishmaniasis
Cell mediated immunity is crucial in protecting against the following infectious agents…
(people without CMI (AIDS pt) get these)
-Intracellular bacteria e.g. M.tuberculosis
-Large viruses e.g. Pox and Herpes viruses
-Fungi e.g. Candida albicans.
Pneumocystis
-Parasites e.g. Toxoplasma
Delayed Hypersensitivity may cause a number of important auto-immune diseases…
Insulin-dependent diabetes mellitus (IDDM) Rheumatoid arthritis Multiple sclerosis Crohn’s Disease Psoriasis Celiac Disease
^ all primarily caused by T-cell attack, may be followed by secondary AutoAb production (once destroy tissue –> new antigens released –> Abs made to these)
A 25-year-old woman develops vaginal candidiasis following a course of antibiotics for acne. A small dose of candida extract is injected into the skin of her arm and a red, raised wheal develops at the site in 48 hours. Rxn shows
Normal CMI
Most immunodeficiency disorders are due to
B cell defects
A crucial part of innate immunity is the involvement of neutrophils. What are their functions?
Chemotaxis (C3a/C5a –> chemokines)
Phagocytosis (Opsonization: IgG + C3b enhance this)
Killing (Lysosomal granules contain many bactericidal agents)
Defects of Neutrophil function (Inability to mount a normal inflammatory response)
- Neutropenia- low neutrophil count e.g. patients receiving chemotherapy
- Defective opsonization (IgG deficiency, C3b deficiency *rare)
- Non-killing neutrophils
- Chronic granulomatous disease (CGD)
Chronic granulomatous disease (CGD)
Non-killing neutrophils
- X-linked (*males)
- defect in cytochrome b and NADPH oxidase –> no superoxide anion prod, cant kill staph
- recurrent infection with abscess of skin, lymph nodes, CHRONIC GRANULOMAS
Neutropenia
- Defective opsonization (mediated by IgG + C3b).
- Defective inflammatory response (chemotaxis by C3a + C5a).
- Defective phagocytosis.
Under normal circumstances, ______________ in the neutrophil cytoplasm collide with the phagosome and release their granules containing numerous bactericidal enzymes and ____________.
lysosomal granules
superoxide anion.
Leukocyte Adhesion Deficiency (LFA-1 deficiency)
- Neutrophils fail to emigrate out of vessels towards the ag (no sticking to endothelial cells)
- Failure of CD8+ cells to bind to target cells
- Recurrent bacterial infection
- Failure to heal wounds (Umbilicus)
Chediak Higashi Syndrome
- Giant Lysosomal Granules
- Defective phagosome-lysosomal fusion in neutrophils
- Recurrent infection
Neutrophil defect immune deficiencies
- Neutropenia
- CGD
- Leukocyte Adhesion Deficiency (LFA-1)
- Chediak-Higashi Syndrome
X-Linked Agammaglobulinemia
- “Brunton’s agammaglobulinemia”
- Absent IgG, IgA and IgM
- Pre-B cells in marrow, but no mature B-cells
- Absent or very small tonsils and lymph nodes
- Btk mutation (TYR KINASE imp for light chain rearrang.)
- Absent germinal centers in lymph nodes, absent B-cells in blood
- recurrent infections
*boys
Serum electrophoresis from 1) a normal person and 2) a patient with X-linked agammaglobulinemia
(absent gamma-globulin band)
Management of X-Linked Agammaglobulinemia
Avoid infections where possible
Abx
Intravenous immunoglobulin (IVIG) every 3 weeks
3 weeks for IVIG to drop, then give another shot
IgA Deficiency
- Common 1:700
- many pt asymptomatic
- Pt w/ associated IgG2 or IgG4 deficiency –> severe respiratory and GI infections
- IVIG is not usually helpful
Hyper IgM syndrome
- mut CD40L gene (on TCell)
- Failure of isotype switching
- Only IgM and IgD. NO switch to IgG, IgA or IgE
- NO germinal centers. Most cells are T cells.
- Recurrent infections
Transient Hypogammaglobulinemia of Childhood
- Delay in the production of normal Abs
- B-cells are present
- Transient ability to prod IgG
- Cause is unknown, may be due to deficiency in #/function of hyperTcells
- Resolves with time
Common Variable Immunodeficiency
- not common. Appears in teens/adults
- Low serum levels of all immunoglobulins
- B-cells are present
- Increased susceptibility to infections
- Defect unknown (poss defect B-cells –> plasma cells)
- tx:IVIG
Humoral deficiency
Di George Syndrome
(chromosome 22q11.2 deletion syndrome (22qDS)
1) Cardiac anomalies
2) Hypoplastic thymus or complete ABSENCE of the thymus.
3) Hypocalcemia (resulting from parathyroid hypoplasia).
4) Facial abnormalities e.g. cleft palate
Majority of patients with DGS have deletions in chromosome 22q11.2.
- recurrent infections with intracellular bacteria,
fungi, large viruses (also pyogenic organisms bc lack of T-cell help for B-cells)
Di George Syndrome CATCH 22
Cardiac abnormality Abnormal facies Thymic aplasia Cleft palate Hypocalcemia.
Patients with Di George syndrome will have:
A) Decreased numbers of surface IgM and IgD positive B-cells
B) Normal serum IgE levels
C) Normal serum anti-influenza IgG levels after immunization with the influenza vaccine
D) Normal ability to produce acute phase proteins such as CRP
E) Normal IL-2 production
D
Severe Combined Immunodeficiency
- Numerous forms of SCID that can result from any one of several genetic defects.
- Both humoral and cell mediated immunity are defective.
- Patients are susceptible to all infectious agents (severe oral esophageal/nail candidiasis)
Tx: reconstitution of immune system with stem cell transplantation *beware of GVH
The commonest form of SCID
- mutation of the common-chain of the IL-2 Receptor
- X-linked severe combined immunodeficiency
Adenosine deaminase (ADA) deficiency
Form of SCID
Bare lymphocyte syndrome
Form of SCID Cells lack class I or II MHC molecules
Abnormal signal transduction leading to SCID
1) Mutations of protein kinases e.g. JAK3 or ZAP 70
2) Mutations of RAG1 and RAG2
3. ) Mutations of CD3
4) Defective cytokine production
Mutations of the CD3 molecule
Defective Cytokine production
Can lead to …
SCID
Wiskott Aldridge Syndrome
Immunodeficiency
Thrombocytopenia (low platelet count) - purpuric spots
Eczema (Elevated IgE, type I allergic rxn)
Recurrent infections
tx: stem cell transplant
Ataxia Telangiectasia
Defective DNA repair, causing a type of SCID.
Ataxia
Telangiectasia (of eye)
Immunodeficiency
no curative tx
Secondary Immunodeficiency (Defective humoral immunity)
Lymphoma
Myeloma
Burns
(loss of Ig in serum)
Secondary Immunodeficiency (Defective Cell mediated Immunity)
Patients taking Immunosuppressive drugs
Malnutrition
Viral infections especially HIV
Ageing
Acquired Immunodeficiency Syndrome (HIV)
HIV virus infects the CD4 cell
Viral gp120 binds to the CD4 molecule
Gp41 binds to the chemokine receptor CCR5
T cells drop dramatically
Clinical course of HIV disease
4-6 weeks T cells drop to about half of what they should be.
Then stabilize at about half their normal level (clinical latency)
Virus goes sky high, drops, continues for months/years (clinical latency), then suddenly goes up. Infections, death.
Laboratory diagnosis of HIV
1) Can detect HIV antigen or antibody in the blood
2) Reversal of the CD4:CD8 ratio. This ratio is normally approximately 2:1
3) Measure serum levels of HIV RNA to follow progress of the disease.
The commonest immunodeficiency ….
Ageing is associated with significant and continuous immune deficiency
Decreasing number and function of many cell types including, neutrophils, antigen presenting cells, NK cells, and T-cells
Specific immunodeficiency to papilloma virus
causing very severe warts
Pt responded normally to PPD and to other delayed hypersensitivity skin tests (normal cell mediated immunity)
cause unknown
Chronic mucocutaneous Candidiasis
Lack of IL-17 production or Autoantibody to IL-17
Arthus rxn
localized TIII HS
Injected Ag into individual with pre-formed antibody, causing localized
neutrophil invasion and inflammation.
LATER T-cell infiltration, cytokines
Hypersensitivity type that causes cytokine production by T-cells
Type IV Type III (T-cell infiltration after neutrophil-complement activation)
NOTE: Type I cytokines are produced also via eiosinophls, macrophages, mast cells
B-cell defect immune deficiencies
- Brunton’s (X-linked) aggamaglobulinemia
- IgA deficiency
- Hyper-IgM syndrome
- Transient Hypogammaglobulinemia of Infancy
- Common Variable Immunodeficiency
T-cell/SCID defect
- DiGeorge Syndrome
- T-cell Activation Defects
- Severe Combined Immunodeficiency
- Bare Lymphocyte Syndrome
- Wiskott-Aldritch Syndrome
- Ataxia Telangiectasia
To diagnose type II HS…
measure specific serum IgG Abs
