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)
