1. C1 binds to the Fc region of the antibody bound to antigen
2. C1q, C1r, and C1s clump together on the Fc region to become the C1 esterase
3. C1 esterase cleaves C4 into C4a (which is released) and C4b (which binds to the complex on the antibody)
4. C14b binds and cleaves C2 into C2a and C2b (which binds to the complex)
5. C14b2b becomes the C3 convertase which cleaves C3 into C3a and C3b
6. C14b2b3b cleaves C5 into C5a and C5b which forms the Membrane Attack Complex (MAC)
What is the MAC?
C5b initiated the complex of C6, C7, C8, and many molecules of C9
incoporation of many molecules of C9 causes further penentration of the lipid bilayer and results in the formation of a transmembrane channel that disturbs the cell's osmotic equilibrium that results in cell lysis
What are the functions of the complement system?
1. Opsonization: phagocytes have a cell surface receptor called the CRI that binds C3b when it is bound to and Ag-Ab complex; this assists in phagocytosis
2. Inflammation: C3a and C5a are chemo attractants which direct the migration of phagocytes towards the site of complement activation; these are also called anaphylatoxins because they cause degranulation of mast cells and basophils whic release histamine and other things that increase capillary permeability
3. Lysis of pathogens: via the MAC; particularly important in destroying Neisseria organisms
4. Viral neutralization
5. Clearance of Immune-Complexes
What is the alternative complement pathway?
activate dby bacterial or viral particles, such as LPS
1. Free-floating C3b binds to foreign microbial products
2. serum factors B and D, as well as properdin (aka Factor P) combine witht he C3b to form C3BbBP which is a C3 convertase
3. This complex splits C3 and continues the complement cascade
this pathway is primed and ready to go, and it is inhibited by Factor H and Factor I which bind C3b to inactivate it.
What is the Lectin Pathway of Complement Activation?
Activated by mannose resiudes found on the surface of many bacteria
Mannose-binding-lectin (MBL) binds lectin, then Mannose-associated serine proteases 1 and 2 bind
This complex cleaves C4 and C2 to make the C4b2b which cleaves C3 and activates the cascade
What is C1 esterase inhibitor (C1 INH)?
a protein that inhibits the first step in the activationof the classical complement pathway
binds C1r and C1s so they dissociate from C1q to prevent complement activation
absence of this protein results in Hereditary Angioedema
C1q, C1r, C2, C4: SLE possibly due to the inability to clear immune complexes
C5: bacterial infection, but not as severe as the above deficincy
C6, C7, or C8: Neisserial Infection
Alternative pathway proteins: recurrent pyogenic infections
MBL pathway: recurrent infection in childhood
C1 INH: Hereditary angioedema (HAE)
What is HAE?
deficient C1 INH
characterized by localized edema in the skin and mucosa
recurrent attacks of swollen face and limbs, pain in the abdomen, and swelling of the larynx
can be aggrivated by trauma or menses
can be treated with pure C1 INH or with certain androgens that can stimulate the liver to make more
What is an adjuvant?
substances distinct from antigen that enhance T-cell activiation by promoting the accumulation of APCs at the site of antigen exposure
might increase cytokine production and expression of co-stimulator molecules by APCs
significantly increases antibody response
What is CD40?
a co-stimulator molecule on B-cells that binds to the CD40 ligand on T-cells
needed to induce antibody isotype switching
How are T-cells regulated?
1. CTLA-4: molecule expressed on the surface of t-cells that is also a receptor for B7 and it competes with CD28 for binding to B7; when bound to B7 it delivers an inhibitory signal to the T-cell
2. Activation Induced Cell Death: repeated activation of T-cells leads to the co-expression of a death receptor; they normally have Fas ligand but they will begin to express Fas which induced apoptosis
3. T-regulator Cells (Tregs): CD25+CD4+ cells that develop during positive selection in the thymus; express CTLA-4; may also secrete supressive cytokines such as IL-10 and TNF-beta
4. Cytokine Mediated Regulation: INF-gamma produced by TH1 cells inhibits proliferation of TH2 cells; IL-4 from TH2 cells inhibits the proliferation of TH1 cells
What is anergy?
the inactivation of t cells that occurs when these cells recognize antigens without adequate levels of costimulators that are needed for full T cell activation
What is central tolerance?
un-responsiveness to self-antigens
the self-tolerance that occurs in the thymus during negative selection
What is peripheral tolerance?
when t-cells with central tolerance escape the thymus and migrate to the periphery
they are dealt with by clonal deletion (antigen-specific cells are removed by apoptosis) or clonal anergy (antigen-specific cells are present but unable to respond
What is fetal tolerance?
if you implant something foreign into a fetus, it wll not react because its thymus is still developing and it will treat the donor tissue as self
What are the ways that adult tolerance may be produced?
interaction of T cells with antigen in the absence of thew co-stimulatory signals; administer anti-B& and anti-CD28
high dose tolerance by administering proteins systemically in high doses
oral tolerance by introducing protein antigens administered orally
What are the immunological factors that may contribute to autoimmunity?
1. Exposure of Hidden/Sequestered Antigen: certain tissues antigens are sequestered from the thymus during devlopment so they are not recognized as self; exposure of mature t cells to such normally sequestered antigens at a later date could result in their activation, ex. sympathetic ophthalmia (arrow to the eye)
2. Polyclonal Lymphocyte Activation: some viruses and bacteria can activate B-cells non-specifically; super-antigens over-activate t-cells
3. Abnormal Lymphocyte Regulation/ Excessive cytokine production: may abnormally activate lymphocytes; ex. IL-2 may activate a lot of T-cells and CD28 and B7 may activate many B-cells
4. Defective Fas-Fas L Interaction: mature peripheral T cells do not die and they can continue to proliferate and produce autoimmune disease
5. Defective TREGS: inability to turn down the t-cell response
6. Balance between CTLA-4 and CD28: inability to terminate the immune response may lead to overactive t-cells
What evidence is there that there may be genetic factor for autoimmune disease?
1. autoimmune diseases are more common in certain families; in-bred strains of mice have been developed that spontaneoulsy develop autoimmune disease
2. certain auto-immune diseases occur in individuals with certain HLA alleles
3. increased incidence in twins
What are the microbial factors that lead to autoimmunity?
1. Molecular Mimicry: some microbes share similar or identical antigens with humans, so onfection leads to production of cross-reactive antibodies or t-cells that attack self tissue; ex. rheumatic fever after strep throat
2. Abnormal activation of Lymphoid Cells: microbes and their superantigens may inappropriately activate B cells or T cell that are not specific; also may stimulate them to secrete cytokines which induces inappapropriate class II MHC expression
3. Release of Hidden Antigens: microbes may cause tissue damage that release hidden antigens
4. Microbes may function as adjuvants: usually when the APC process and present tissue proteins with bacteria; the bacteria induce the formation of MHC class II molecules but the T-cells recognize the self protein with it then begin to attack it
What evidence is there for the presence of a hormonal factor to autoimmune disease?
they are much more common in females
What are the four types of grafts?
Autograft: one person to the same person
Syngraft: onre person to a genetically identically recipient, ie a twin
Allograft: one person to a genetically different recipient
Xenograft: donor and recipient are of different species
Cancer Immunotherapy options
Imiquimod: activates TLR7 to cause a localized inflammatory response for HPV and basal cell carcinomas
BCG: induces a localized inflammatory response for superficial bladder cnacer
Cytokine treatment: IL-2 and IFN-gamma have been used to treat advanced melanoma and renal cell carcinoma; the network is complex
Immunization: vaccinate against cancer causing viruses; or immunize with whole tumor cells; problem is that tumors are weakly immunogenic so they may not activate a response; may introduce a co-stimulator like B7 to make them more immunogenis
Monoclonal antibodies: target tumor associated antigens; examples include anti-CD20 for B cell lymphoma, anti EGFR for colo-rectal cancers and anti-HER2/neu for breast and ovarian cancer
Immunotoxins: attach a plant or bacterial toxin to a tumor directed antibody
Radioimmunoconjugates: carry a raditation source to the tumor site for therapy or diagnosis
Immediate Hypersensitivity (Type I)
aka allergic reaction; IgE-mediated release of histamine from mast cells and basophils
Sensitization: when atopic individuals (someone genetically capable of making IgE) are exposed to a specific antigen; APCs process it and present it to TH1 or TH2 cells; in the presence of IL-4 TH2 cells will be activated and will make more IL-4 and IL-13 which acts on B cells to make IgE; the Fc region binds to mast cells and basophils and they are primed and move into the mucosa and submucosa
Early Phase: Allergen binds to the IgE on the surface of the cell and the cells degranulate and release inflammaotry mediators
Late Phase: the things release in the early phase recruit leukocytes to the area; IL-3 for basophils, IL-4 makes more IgE and TH2 cells, IL-5 stimulate proliferation and recruitment of eosinophils and basophils, TNF-alpha starts the complement cascade, GM-CSF makes more granulocytes and PAF increases vascular permeability; all of this results in a recurrence of symptoms; eosinophils release chemicla mediators, toxic oxygen products and cytolytic enzymes that damage airways; they also make leukocyte attractants and endothelial cell adhesion molecules
Test: Skin prick tests
Treatment: eliminate antigen from environment, inhibit degranulation and reduce inflammation; antihistamines, bronchodialators, corticosteroids; monoclonal anticodies against IgE (Omalizumab); desensitization (raise the level of IgG antibodies in the serum)
What are the imflammatory mediators released from Mast cells during Type I hypersensitivity and what do they do?
Histamine: bronchioconstriction, vasodilation, increase vascular permeability, stimulate nerve endings, and stimulate mucous secretions in airway
Platelet Activating Factor: constrict bronchial airways and vasodilation
All leads to wheezing and difficulty breathing, local redness, swelling, itching, congestion
Cytotoxic Hypersensitivity (Type II)
IgG and IgM antibodies bind to antigens which are structural components of circulating cells or fixed tissues
Can cause cell destruction via:
1. Complement pathway: the antibodie sinteract with antigen on host cell membranes and the classical complement pathway is activated, MAC kills the cell
2. C3a and C5a are released from complement activation and they are chemoattractants for inflammation
3. Binding of IgG and C3b to cells enhance phagocytosis (opsonization)
4. Antibody coated cells are targetted by NK cells
What are some clinical examples of Cytotoxin hypersensitivity reactions?
Autoimune Hemolytic Anemia: autoantibodies against RBCs; destroyed via complement or phagocytosis
Autoimmune thrombocytopenia: autoantibodies againts platelets; when bound to IgG they are removed from circulation by macrophages in the spleen and liver
Hyperacute Graft Rejection: pre-formed antibodies in the circulation against antigens on the transplanted tissue; triggers the blood clotting cascade leading to ischemia and necrosis of the graft
Goodpasture's Syndrome: autoantibodies against glomerular and alveolar basement membranes; damage to the kidneys and the lungs
Myasthenia Gravis: autoantibodies against the AChR at neuromuscular joints; antibody attaches to the receptors and is taken into the muscle cell; leads to sever muscle weakness; can be treated with plasmaphoresis
Graves Disease: Autoantibodies against the TSH receptor; acts as an agonist and constitutively turns on the thryoid gland and results in hyperthryoidism
Immune Complex Hypersensitivity (Type III)
antigen bound to antibody (immune complexes) circulate throughout the body and deposit in tissues
they can bind complement leading to inflammation; the C3a and C5a also attarct neutrophils to the site which release degredative enzymes that damage tissues
Clinical examples of systemic immune complex disease
Systemic Lupus Erythematosus (SLE): involves antibodies to several nuclear components including DNA; immune complexes deposit in many tissue and affect many organ systems; test for antinuclear antibodies in the serum
Post-streptococcal glomerulonephritis: anti-strep antibodies complex with strep antigens in the blood and get stuck in the glomerular capillary wall
Serum sickness: make antibodies to foreign serum after treatment with horse anitbodies for something else (like snake venom); immune complexes deposit in various tissue but especially in the joints, arteries, and glomeruli
Drug reactions: antibodies are commonly produced against drugs and when they combine with the drug they form an immmune complex that deposits in the arteries causin vasculitis; NOTE: penecillin cna cause Type I, II and IV reactions
Clinical examples of localized immune complex diseases
Also known as the Arthus Reaction: localized inflammation mediated by IgG bound to antigen
1. Inoculation sites: usually for booster shots; there is already IgG present so it binds to the antigen and recruits neutrophils that damage vessels
2. Farmer's lung: repeated exposure to moldy hay causes a farmer to make IgG to the mold spores; later inhalation of the spores causes inflammation; it can also result in delated hypersensitivity
Delayed Hypersensitivity (Type IV)
a form of cell-mediated immunity (used T cells activated my macrophages); can be damaging to host when the t cells release inappropriately large amounts of cytokines
Sensitization Phase: APCs process antigen and present it to TH1 cells which causes an increase in the circulating TH1 cells specific to that antibody
Effector Phase: when exposed to antigen, the TH1 cells release cytokines that recruit and activate macrophages and other inflammatory cells; CD8 T cells also get activated and all of these things combined cause tissue damage
The effector response is mediated by : IL-2 (promotes T cell proliferation), IFN-gamma (activated macrophages; release other inflammatory factors), IL-1 and TNF (uregulate endothelial cell adhesion and cause them to release IL-8 to attract more leukocytes)
2. Mantoux reaction: TB PPD skin test; bump full of monocytes and macrophages, not neutrophils
3. Chronic Infections: lesions from tuberculosis, leprosy, or syphilis; skin rashes in smallpox, measles, lesions caused by herpes, fungal disease, or parasitic disease like leishmania
4. Autoimmune disease: T cells specific for iselt cells in IDDM, specific for unknown antigens in joint synovium in rheumatoid arthiritis, specific for myelin in MS, infiltration fo t cells in Crohn's disease, hyperproliferation of keratinocytes in psoriasis due to cytokines released by TH1 cells; t cells specific for wheat in Celiac's disease
Congenital defects in neutrophil response
1. Neutropenia: inadequate numbers to mount an immune response
2. Defective opsinization: can be caused from a defect in IgG or C3b
3. Chronic granulomatous disease (CGD): X-linked condition; defect in cytochrome b and NADPH oxidase makes them unable to generate superoxide in their phagosomes; results in granulomas in the skin, lymph nodes and other organs (accumulationg of monocytes, macrophages, and neutrophils)
4. Leokocyte Adhesion Deficiency (LFA-1 deficiency): failure of neutrophils to migrate out of vessels at the site of antigen exposure; causes recurrent bacterial infections and inability to heal wounds such as the umbilical cord
5. Cediak Higashi Syndrome: giant lysosomal granules that can't move; affects every organ
Primary Humoral immunodeficiency disorders
1. X-linked/Bruton's Agammaglobulinemia: Pre-B cells are in the bone marrow but they do not mature or make IgG, IgA, or IgM; absent or very small tonsils and lymph nodes becuase they do not have germinal centers of b cells; mutation of the Burton's tyrosine kinase gene needed fo rlight chain rearrangement; use antibody to CD19 to test for B cells; recurrent infections with extracellular pathogens; treatment: avaoid pathogens, use antibiotics, IVIG every three weeks
2. IgA deficiency: very common and often undiagnosed; when combined with IgG2 or IgG4 deficiency it is more serious; IVIG doesn't help because IgA cant get into the serum; common symptoms include diarrhea and cough
3. Hyper-IgM Syndrome: mutation of the CD40 ligand that is on T cells and needed for B cells to do isotype switching; patients do not have IgG, IgA or IgE so they get recurrent infections; dont have germinal centers
4. Transient Hypogammaglobulinemia of infancy: delay in the normal production of antibodies and maternal ones only last 3-6 months; B-cells are present; cause is unknown
5. Common Variable Immunodeficiency: low serum levels of all immunoglobulins; cuase unknown; recurrent infections of all types; example is honeymoon cystitis
Primary T cell immunodeficiencies
1. DiGeorge Syndrome: deletion on chromosome 22 that causes defective development of the thymus; C (cardiac abnormalities); A (abnormal facial features); T (thumic aplasia); C (cleft palate); H (hypoglycemia); recurrent infections with intracellular bacteria, fungi, and large viruses because of the dampered CD8 t cell response; recurrent pyogenic infections too because t cells are needed to stimulate b cells
2. T cell activation defects: can be caused by abnormal CD3 expression, abnormal signal transduction, defective cytokine production or defective IL-2 receptor expression
numerous forms of the disease and many causes; all aspects of the immune system are affected so patients are susceptible to all types of infection
most common form is a defect in the IL-2 receptor; this is X-linked SCID
ADA deficiency: accumulation of metabolites is toxic to proliferatoin of B and T cells
bare lymphocyte syndrome: they are missing MHC molecules
Abnormal signal trandsuction: can be mutations of protein kinases like JAK and ZAP or RAG1 or 2 so there is no isotype switching
Missing CD3: no signal transduction
Treatment: stem cell transplants but must be exact HLA match
Wiskott Aldridge Syndrome: leads to thrombocytopenia; X-linked; increased IgE leads to eczema; treated by stem cell transplant
Ataxia Telangiectasia: ataxia (drunken walk) and telangiactasia (little spider-looking patterns of vessels); no treatment
Humoral: lymphoma, myeloma and burns
Cell mediaited: people on immunosuppresive durgs; protein malnutrition; viral infections (like HIV: has gp120 which binds CD4 and gp41 which binds CCR5 to enter the cell)
Aging: decreased numbers of neutrophils, APCs, NK cells, and t cells