Immunology Flashcards
Lymph node
A secondary lymphoid organ that has many afferents, 1 or more efferents. Encapsulated, with trabeculae. Functions are nonspecific filtration by macrophages, storage of B and T cells, and immune response activation.
Follicles of lymph nodes
Site of B-cell localization and proliferation. In outer cortex. Primary follicles are dense and dormant. Secondary follicles have pale central germinal centers and are active.
Medulla of lymph nodes
Consists of medullary cords (closely packed lymphocytes and plasma cells) and medullary sinuseses. Medullary sinuses communicate with efferent lymphatics and contain reticular cells and macrophages.
Paracortex of lymph nodes
Houses T cells. Region of cortex between follicles and medulla. Contains high endothelial venules through which T and B cells enter from blood. Not well developed in patients with DiGeorge syndrome. Paracortex enlarges in an extreme cellular immune response (eg viral infection).
Lymph drainage of head and neck
cervical lymph node
Lymph drainage of lungs
hilar lymph node
Lymph drainage of trachea and esophagus
mediastinal lymph nodes
Lymph drainage of upper limb, breast, skin above umbilicus
Axillary lymph nodes
Lymph drainage of liver, stomach, spleen, pancreas, and upper duodenum
celiac lymph nodes
Lymph drainage of lower duodenum, jejunum, ileum, colon to splenic flexure
superior mesenteric lymph nodes
Lymph drainage of colon from splenic flexure to upper rectum
inferior mesenteric lymph nodes
Lymph drainage of lower rectum to anal canal (above pectinate line), bladder, vagina (middle third), prostate
internal iliac lymph nodes
Lymph drainage of testes, ovaries, kidneys, uterus
para-aortic lymph nodes
Lymph drainage of anal canal (below pectinate line), skin below umbilicus (except popliteal territory), scrotum
superficial inguinal lymph nodes
Lymph drainage of dorsolateral foot and posterior calf
popliteal lymph nodes
right lymphatic duct
drains right side of body above the diaphragm
thoracic duct
drains everything but the right side of body above the diaphragm
Sinusoids of spleen
Long, vascular channels in red pulp with fenestrated “barrel hoop” basement membrane. T cells are found in the periarteriolar lymphatic sheath (PALS) within the white pulp of the spleen. B cells are found in follicles within the white pulp of the spleen. The marginal zone, in between the red pulp and white pulp, contains APCs and specialized B cells, and is where APCs capture blood-borne antigens for recognition by lymphocytes. Red pulp is found peripherally, and the white pulp is found centrally. Macrophages found nearby in spleen remove encapsulated bacteria.
Splenic dysfunction (eg postsplenectomy, sickle cell disease)
a decrease in IgM leads to a decrease in complement activation causing a decrease in C3b opsonization and creating an increase susceptibility to encapsulated organisms. Common infections include (SHiNE SKiS): Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis, Escherichia coli, Salmonella spp., Klebsiella pneumoniae, Group B Streptococci.
Postsplenectomy histology
Howell-Jolly bodies (nuclear remnants), target cells, thrombocytosis (loss of sequestration and removal), and lymphocytosis (loss of sequestration).
Thymus
Site of T cell differentiation and maturation. Encapsulated. THymus is derived from the THird pharyngeal pouch. Lymphocytes of mesenchymal origin. Cortex is dense with immature T cells; medulla is pale with mature T cells and Hassall corpuscles containing epithelial reticular cells. T cells= Thymus. B cells=Bone marrow
Innate immunity
Made up of neutrophils, macrophages, monocytes, dendritic cells, natural killer cells (lymphoid origin), complement. It is germline encoded. Resistance to the innate immunity through generations; does not change within an organism’s lifetime. Response to pathogen is non-specific and occurs rapidly (minutes to hours). Physical barriers apart of the innate immunity includes epithelial tight junctions and mucus. Secreted proteins include lysozyme, complement, c-reactive protein (CRP), defensins. Key features in pathogen recognition includes toll-like receptors (TLRs), which are patteren recognition receptors that recognize pathogen-associate molecular patterns (PAMPs). Examples of PAMPs include LPS (gram-negative bacteria), flagellin (bacteria), ssRNA (viruses).
Adaptive immunity
Made up of T cells, B cells, and circulating antibodies. It has variation through V(D)J recombination with lymphocyte development. Microbial resistance is not inheritable. Response to pathogens is highly specific and is refined over time. It develops over long periods but memory response is faster and more robust. Immunoglobulins are secreted. Memory cells include activated B and T cells; subsequent exposure to a previously encountered antigen leads to a stronger and quicker immune response.
MHC I and II
MHC encoded by HLA genes. Present antigen fragments to T cells and bind T-cell receptors (TCRs).
MHC I
Loci include HLA-A, HLA-B, HLA-C. Binds TCR and CD8. It is expressed on all nucleated cells, but are not expressed on RBC’s. They present endogenously synthesized antigens (eg viral or cytosolic proteins) to CD8+ cytotoxic T cells. Antigen peptides are loaded onto MHC I in RER after delivery via TAP (transporter associated with antigen processing). A component of MHC class I molecules is beta2-microglobulin.
MHC II
Loci include HLA-DR, HLA-DP, HLA-DQ. Binds to TCR and CD4. They are expressed on APCs. They present exogenously synthesized antigens (eg bacterial proteins) to CD4+ helper T cells. Antigens are loaded following release of invariant chain in an acidified endosome. A polypeptide involved in the formation and transport of MHC class II protein is invariant chain.
HLA-A3
Associated with hemochromatosis.
HLA-B27
Associated with Psoriatic arthritis, Ankylosing spondylitis, arthritis of Inflammatory bowel disease, Reactive arthritis (formerly Reiter syndrome). (PAIR). Also known as seronegative arthropathies.
HLA-DQ2/DQ8
Associated with celiac disease
HLA-DR3
associated with diabetes mellitus type 1, SLE, Graves disease, Hashimoto thyroiditis.
HLA-DR2
Multiple sclerosis, hay fever, SLE, Goodpasture syndrome
HLA-DR4
Rheumatoid arthritis, diabetes mellitus type 1. There are 4 walls to a “rheum”
HLA-DR5
Associated with pernicious anemia, which leads to vitamin B12 deficiency and Hashiomoto thyroiditis.
Natural killer cells
Use perforin and granzymes to induce apoptosis of virally infected cells and tumor cells. They are lymphocyte members of innate immunity. Their activity is inhanced by IL-2, IL-12, IL-alpha, and IL-beta. They are induced to kill when exposed to a nonspecific activation signal on target cell and/or to an absence of class I MHC on target cell surface. Also kills via antibody-dependent cell-mediated cytotoxicity (CD16 binds Fc region of bound Ig, activating the NK cell).
B-cell functions
They recognize antigens and undergo somatic hypermutation to optimize antigen specificity. They also produce antibodies and differentiate into plasma cells to secrete specific immunoglobulins. They also maintain immunologic memory. Memory B cells persist and accelerate future response to antigen.
T-cell functions
CD4+ T cells help B cells make antibodies and produce cytokines to recruit phagocytes and activate other leukocytes. CD8+ T cells directly kill virus-infected cells. Delayed cell-mediated hypersensitivity (type IV). Acute and chronic cellular organ rejection. Rule of 8: MHC II X CD4=8; MHC 1 X CD8=8.
Differentiation to Th1 cell from helper T cells
requires IL-12
Differentiation to Th2 cell from helper T cells
requires IL-4
Differentiation to Th17 cell from helper T cells
TGF-beta and IL-6
Th1 cell
A helper T cell. Secrete IFN-gamma. Activates macrophages and cytotoxic T cells. They are activated by INF-gamma and IL-12. They inhibited by IL-4 and IL-10 (from Th2 cells). Macrophages release IL-12, which stimulates T cells to differentiate into Th1 cells. Th1 cells release IFN-gamma to stimulate macrophages. Helper T cells have CD4, which binds to MHC II on APCs.
Th2 cell
Secretes IL-4, IL-5, IL-10, and IL-13. They recruit eosinophil for parasite defense and promotes IgE production by B cells. They are activated by IL-4. They are inhibited by IFN-gamma (from Th1 cell).
Cytotoxic T cells
They kill virus-infected, neoplastic, and donor graft cells by inducing apoptosis. They release cytotoxic granules containing preformed proteins (eg perforin, granzyme B). Cytotoxic T cells have CD8, which binds to MHC I on virus-infected cells.
Regulatory T cells
They help maintain specific immune tolerance by suppressing CD4 and CD8 T cell effector functions. They are identifiable by expression of CD3, CD4, CD25, and FOXP3. Activated by regulatory T cells produce anti-inflammatory cytokines (eg IL-10, TGF-beta).
T and B cell activation
Antigen-presenting cells (APCs) include B cells, macrophages, and dendritic cells. Two singals are required for T-cell activation, B-cell activation, and class switching.
Steps for naive T-cell activation
- Dendritic cell (specialized APC) samples and processes antigen. 2. Dendritic cell migrates to the draining lymph node. 3. Foreign antigen is presented on MHC II and recognized by TCR on Th (CD4+) cell. Antigen is presented on MHC I to Tc (CD8+) cell. 4. “Costimulatory signal” is given by interaction of B7 and CD28 (signal 2). 5. Th cell activates and produces cytokines. Tc cell activates and is able to recognize and kill virus-infected cell.
Steps B-cell activation and class switching
- Th-cell activation as above. 2. B-cell receptor- mediated endocytosis; foreign antigen is presented on MHC II and recognized by TCR on Th cell (signal 1). 3. CD40 ligand (CD40L) on Th cell (signal 2). 4. Th cell secretes cytokines that determine Ig class switching B cell. B cell activates and undergoes class switching, affinity maturation, and antibody production.
Antibody structure and function
Fab (variable) region consisting of light (L) and heavy (H) chains recognizes antigens. Fc region of IgM and IgG fixes complement. Heavy chain contributes to Fc and Fab regions. Light chain contributes only to Fab region.
Fab region of antibodies
Fragment that does the Antigen Binding. Determines idiotype creating a unique antigen-binding pocket; only 1 antigenic specificity expressed per B cell.
Fc region of antibodies
This region is constant, with carboxy terminal. It also binds complement. Also has carbohydrate side chains. It determines isotype (IgM, IgD, ect).
Generation of the diverse region in antibodies
Random recombination of VJ (light-chain) or V(D)J (heavy chain) genes. Random combination of heavy chains with light chains. Somatic hypermutation (following antigens stimulation). Addition of nucleotides to DNA during recombination by terminal deoxynucleotidyl transferase.
Immunoglobulin isotypes
Mature B cells express IgM and IgD on their surfaces. They may differentiate in germinal centers of lymph nodes by isotype switching (gene rearrangement; mediated by cytokines and CD40L) into plasma cells that secrete IgA, IgE, or IgG.
IgG
Main antibody in secondary (delayed) response to an antigen. Most abundant isotype in serum. Fixes complement, crosses the placental (provides infants with passive immunity), opsonizes bacteria, neutralizes bacterial toxins and viruses
IgA
Prevents attachment of bacteria and viruses to mucous membranes; does not fix complement. Monomer in circulation or dimer when secreted. Crosses epithelial cells by transcytosis. Produced in GI tract (eg by Peyer patches) and protects against gut infections (eg Giardia). Most produced antibody overall, but has a lower serum concentration. Released into secretions (tears, saliva, mucus) and breast milk. Picks up secretory component from epithelial cells before secretion.
IgM
Produced in the primary (immediate)response to an antigen. Fixes complement but does not cross the placenta. It also acts as the antigen receptor on the surface of B cells. They are monomers on B cell and pentamers when secreted. The pentamer structure allows for avid binding to an antigen while the humoral response evolves.
IgD
It has unclear function. It is found on the surface of many B cells and in the serum.
IgE
It binds to mast cells and basophils; it cross-links when exposed to allergen (two IgE binding the same allergen), thereby mediating immediate (type I) hypersensitivity through release of inflammatory mediators such as histamine. Mediates immunity to worms by activating eosinophils. It has the lowest concentration in serum.
Opsonization by antibody
Antibody promotes phagocytosis
Neutralization by antibody
Antibody prevents bacterial adherence
Complement activation by antibody
Activates membrane attack complex (MAC) and C3b, enhancing opsonization and lysis. Complement binding region is the CH2 region of the Fc.
Differentiation of T cells
T cells precursors are made in the bone marrow and than move to the thymus (at this point they express CD4+, CD8+, and T-cell receptor, which binds MHC I or MHC II) where they undergo positive and negative selection. By the time the T cell reaches the thymic medulla, it is differentiated. They then travel to the lymph node to wait for activation. Cytotoxic T cells kill virus-infected, neoplastic, and donor graft cells. Helper T cells will further differentiate once activated (eg Th1, Th2, Th17).
Positive selection of T cells
Occurs the in the thymic cortex. T cells expressing TCRs (T-cell receptors) are capable of binding surface self MHC molecules survive.
Negative selection of T cells
Occurs in the medulla of the thymus. T cells expressing TCRs with high affinity for self antigens undergo apoptosis.
Thymus independent antigens
Antigens lack a peptide component (eg lipopolysaccharides from gram negative bacteria). They cannot be presented by MHC to T cells. They are weakly or non-immunogenic. Vaccines often require boosters and adjuvants (eg pneumococcal polysaccharide vaccine).
Thymus dependent antigens
Antigens containing a protein component (eg diphtheria vaccine). Class switching and immunologic memory occur as a result of direct contact of B cells with Th cells (CD40-CD40L interaction).
Acute phase reactants
Factors whose serum concentrations change significantly in response to inflammation; produced by the liver in both acute and chronic inflammatory states. It is notably induced by IL-6. Up regulated proteins include CRP, ferritin, fibrinogen, hepcidin, and serum amyloid A. Down regulated proteins include albumin and transferrin.
C-reactive protein
Up regulated during acute phase reactants. It is an opsonin; it also fixes complement and facilitates phagocytosis. It is measured clinically as a sign of ongoing inflammation.
Ferritin
Up regulated during acute phase reactants. It binds and sequesters iron to inhibit microbial iron scavenging.
Fibrinogen
Up regulated during acute phase reactants. It is an coagulation factor, promotes endothelial repair, and correlates with ESR.
Hepcidin
Up regulated during acute phase reactants. It prevents release of iron bound by ferritin, which is the cause of anemia of chronic disease.
Serum amyloid A
Up regulated during acute phase reactants. Prolonged elevation can lead to amyloidosis.
Albumin
Down regulated during acute phase reactants. Reduced concentration conserves amino acids for positive reactants.
Transferrin
Down regulated during acute phase reactants. It is internalized by macrophages to sequester iron.
Complement system
System of hepatically synthesized plasma proteins that play a role in innate immunity and inflammation. Membrane attack complex (MAC) defends against gram-negative bacteria.
Classic complement pathway
It is IgG or IgM mediated. (GM makes classic cars)
Alternative complement pathway
It is activated by microbe surface molecules.
Lectin pathways
It is activated by mannose or other sugars on microbes surface.
C3b
responsible for opsonization (b binds bacteria)
C3a
responsible for anaphylaxis
C4a
responsible for anaphylaxis
C5a
responsible for anaphylaxis and neutrophil chemotaxis.
C5b-9
It is responsible for attracting MAC leading to cytolysis.
Opsonins
C3b and IgG are the two primary opsonins in bacterial defense and enhances phagocytosis. C3b also helps clear immune complexes. Opsonin=to prepare for eating.
Inhibitors of complement system
Decay accelerating factor (DAF, aka CD55) and C1 esterase inhibitor help prevent complement activation on self cells (eg red blood cells).
C1 esterase inhibitor deficiency
Causes hereditary angioedema. Ace inhibitors are contraindicated.
C3 deficiency
Increases risk of severe, recurrent pyogenic sinus and respiratory tract infections; there is an increase susceptibility to type III hypersensitivity reactions.
C5-C9 deficiencies
Terminal complement deficiency increases susceptibility to recurrent Neisseria bacteremia.
DAF (GPI-anchored enzyme) deficiency
Causes complement- mediated lysis of RBCs and paroxysmal nocturnal hemoglobinuria.
Important cytokines
Hot T-bone stEAK: IL-1: fever (hot), IL-2: stimulates T cells, IL-3: stimulates bone marrow, IL-4: stimulates IgE production, IL-5: stimulates IgA, IL-6 stimulates aKute-phase protein production.
IL-1
Secreted by macrophages. Also called osteoclast-activating factor. It causes fever, acute inflammation. It activates endothelium to express adhesion molecules. Induces chemokine secretion to recruit WBCs.
IL-2
It is secreted by all T cells. It stimulates the growth of helper, cytotoxic, and regulatory T cells, and NK cells.
IL-3
It is secreted by all T cells. It stimulates growth and differentiation of bone marrow stem cells. It functions like GM-CSF.
IL-4
It is secreted from Th2 cells. It induces differentiation into Th2 cells. It promotes the growth of B cells and stimulates IgE and IgG production
IL-5
It is secreted from Th2 cells. It promotes the growth of B cells and stimulates IgA production. It also stimulates growth and differentiation of eosinophils.
IL-6
Secreted by macrophages. It causes fever and stimulates production of acute phase proteins
IL-8
Secreted by macrophages. It is major chemotactic factor for neutrophils
IL-12
Secreted by macrophages. It induces differentiation of T cells into Th1 cells and activates NK cells.
TNF-alpha
Secreted by macrophages. It mediates septic shock. It activates endothelium. It causes WBC recruitment and vascular leak. It causes cachexia in malignancy.
Interferon-gamma
It is secreted from Th1 cells. It is also secreted by NK cells in response to IL-12 from macrophages. It also stimulates macrophages to kill phagocytosed pathogens. It also activates NK cells to kill virus-infected cells. It increases MHC expression and antigen presentation by all cells.
IL-10
It is secreted by Th2 cells. It modulates inflammatory response. It also decreases expression of MHC class II and Th1 cytokines (interferon-gamma). It also inhibits activated macrophages and dendritic cells. It is also secreted by regulatory T cells. Both TGF-beta and IL-10 both atTENuate the immune response.
Cytokines secreted by macrophages
IL-1, IL-6, IL-8, IL-12, TNF-alpha.
Cytokines secreted by all T cells
IL-2 and IL-3
Cytokines secreted by Th1 cells
Interferon-gamma
Cytokines secreted by Th2 cells
IL-4, IL-5, and IL-10
Respiratory burst (oxidative burst)
It involves the activation of the phagocyte NADPH oxidase complex (eg in neutrophils, monocytes), which utilizes O2 as a substrate. It plays an important role in the immune response by causing a rapid release of reactive oxygen species (ROS). NADPH plays a role in both the creation and neutralization of ROS. Myeloperoxidase is a blue-green heme-containing pigment that gives sputum its color. Phagocytes of patients with chronic granulomatous disease can utilize H2O2 generated by invading organisms and convert it to ROS. Patients are at an increase risk for infection by catalase positive species (eg S. aureus, Aspergillus) capable of neutralizing their own H2O2, leaving phagocytes without ROS for fighting infections.
Pyocyanin
Produced by P. aeruginosa, functions to generate ROS to kill competing microbes.
Lactoferrin
A protein found in secretory fluids and neutrophils that inhibits microbial growth via iron chelation.
Respiratory burst pathway
- NADPH oxidase converts O2 into a superoxide anion, creating NADP+ from NADPH in the process (deficiency=chronic granulomatous disease). 2. Superoxide dismutase converts a superoxide anion into H2O2. 3. Myeloperoxidase creates HCLO* from H2O2. These first three steps occur in the phagolysosome. 4. Glutathione peroxidase uses H2O2 to convert glutathione (GSH-an antioxidant) into glutathione disulfide (GSSG). This reaction requires selenium. 5. Glutathione reductase recreates GSH using NADPH (from the HMP shunt). This reaction also requires selenium. 6. G6PD replenishes NADPH using glucose-6-p
Interferon alpha and beta
Interfere with viruses. They are apart of innate host defense against both RNA and DNA viruses. Interferons are glycoproteins synthesized by virus-infected cells that act locally on uninfected cells, priming them for viral defense by helping to selectively degrade viral nucleic acid and protein. Essentially results in apoptosis, thereby disrupting viral amplification.
T cell receptor
On all T cells, binds antigen-MHC complex
CD3
On all T cells, it is associated with TCR for signal transduction.
CD28
On all T cells, binds B7 on APC.
CD4
On helper and regulatory T cells
CD40L
On helper T cells, binds to APC (B cells and macrophages)
CD8
On cytotoxic T cells.
CD25
On regulatory T cells
CD19
On B cells.
CD20
On B cells.
CD21
On B cells, the receptor for EBV. You can drink Beer at the (epstein) Barr when you’re 21
CD40
On B cells and macrophages, binds helper T cells (CD40L).
B7
On B cells and macrophages, binds CD28 on T cells.
CD14
On macrophages
Fc and C3b receptors
On macrophages, enhances phagocytosis.
CD16
On NK cells, it binds Fc of IgG
CD56
A unique marker for NK cells.
CD34
On hematopoietic stem cells
Anergy
A state during which a cell cannot become activated by exposure to its antigen. T and B cells become anergic when exposed to their antigens without costimulatory signal (signal 2). Another mechanism of self-tolerance.
Superantigens
Superantigens (S. pyogens and S. aureus) cross-link the beta region of the T-cell receptor to the MHC class II on APCs. Can activate any CD4+ T cell, causing a massive release of cytokine.
Endotoxins
Lipopolysaccharides are on gram negative bacteria and directly stimulate macrophages by binding to endotoxin receptor TLR4/CD14; Th cells are not involved.
Antigenic variation
Some mechaisms for variation include DNA rearrangement and RNA segment reassortment (eg influenza major shift). Classic examples from bacteria include Salmonella (2 flagellar variants), N. gonorrhoeae (pilus protein), and Borrelia recurrentis (relapsing fever). Viral examples include influenza, HIV, and HCV. Examples from parasites include trypanosomes.
Passive immunity
Acquired through receiving preformed antibodies. Onset is rapid. Duration is the life span of antibodies, short (half life of 3 weeks). Examples include IgA in breast milk, maternal IgG crossing placenta, antitoxin, humanized monoclonal antibody. After exposure to Tetanus toxin, Botulinum toxin, HBV, Varicella, or Rabies virus, unvaccinated patients are given preformed antibodies (To Be Healed Very Rapidly)
Active immunity
Acquired through exposure to foreign antigens. Onset is slow. Results are long lasting protections (memory). Examples include natural infection, vaccines (induces an active immune response, humoral and/or cellular, to specific antigens), and toxoid. Combined passive and active immunizations can be given for hepatitis B or rabies exposure.
Live attenuated vaccines
Microorganism loses its pathogenicity but retains capacity for transient growth within inoculated host. Induces cellular and humoral responses. MMR is the only live attenuated vaccine given to person with HIV. It induces strong, often life long immunity. However, it may revert to virulent form. Often contraindicated in pregnancy and immunodeficiency. Examples include measles, mumps, rubella, polio (Sabin), influenza (intranasal), varicella, and yellow fever.
Inactivated or killed vaccine
Pathogen is inactivated by heat or chemicals. Maintaining epitope structure on surface antigens is important for immune response. Mainly induces a humoral response. It is safer than live vaccines. However, it confers a weaker immune response; booster shots are usually required. Examples include Rabies, Influenza (infection) Polio (Salk), hepatitis A (R.I.P. Always)
Type I hypersensitivity
Includes anaphylactic and atopic responses. Free antigen cross-links IgE on presensitized mast cells and basophils, triggering immediate release of vasoactive amines that act at postcapillary venules (i.e. histamine). Reaction develops rapidly after antigen exposure because of preformed antibody. Delayed response follows due to production of arachidonic acid metabolites (eg leukotrienes). First type and Fast. Skin test for specific IgE.
Type II hypersensitivity
It is cytotoxic (antibody mediated). IgM, IgG bind to fixed antigen on what is presumed an enemy cell, leading to cellular destruction. There are three mechanisms: ospsonization and phagocytosis, complement- and Fc receptor-mediated inflammation, and antibody-mediated cellular dysfunction. Type II is Cy-2-toxic. Antibody and complement lead to MAC. Tests include direct and indirect Coombs tests.
Direct Coomb’s test
Detects antibodies that have adhered to patient’s RBCs (eg test for an Rh+ infant of an Rh negative mother.
Indirect Coomb’s Test
Detects serum antibodies that have adhered to other RBCs (eg test an Rh negative woman for Rh positive antibodies).
Type III hypersensitivity
Mediated by immune complexes. Antigen- antibody (IgG) complexes activate complement, which attracts neutrophils; neutrophils release lysosomal enzymes. In type III reaction, imagine an immune complex as 3 things stuck together: antigen-antibody-complement.
Serum sickness
A type III hypersensitivity reaction. An immune complex disease in which antibodies to foreign proteins are produced (takes 5 days). Immune complexes form and are deposited in membranes, where they fix complement (leading to tissue damage). More common than Arthus reaction. Most serum sickness is now caused by drugs (not serum) acting as haptens. Fever, urticaria, arthralgia, proteinuria, lymphadenopathy occur 5-10 days after antigen exposure.
Arthus reaction
A type III hypersensitivity reaction. A local subacute antibody- mediated hypersensitivity reaction. Intradermal injection of antigen induces antibodies, which form antigen-antibody complexes in the skin. Characterized by edema, necrosis, and activation of complement. Antigen-atibody complexes cause the Arthus reaction. Test includes immunofluorescent staining.
Type IV hypersensitivity
It is a delayed (T-cell) mediated type reaction. Sensitized T cells encounter an antigen and then release cytokines (which leads to macrophage activation; no antibody involved). 4th and last=delayed. Cell mediated and therefore it is not transferable by serum. 4 T’s= T cells, Transplant rejections, TB skin tests, Touching (contact dermatitis). Tests include PPD and patch test.
Hypersensitivity types
ACIDS: Anaphylactic and Atopic (type I), Cytotoxic (antibody mediated, type II), Immune complex (type III), Delayed (cell mediated, type IV)
Examples of type I hypersensitivity disorders
Allergic and atopic disorders (eg rhinitis, hay fever, eczema, hives, asthma). Anaphylaxis (eg bee sting, some food/drug allergies). It is immediate, anaphylactic, and atopic.
Examples of type II hypersensitivity disorders
Acute hemolytic transfusion reactions, autoimmune hemolytic anemia, bullous pemphigoid, erythroblastosis fetalis, goodpasture syndrome, graves disease, guillain barre syndrome, idiopathic thrombocytopenic purpura, mysathenia gravis, pemphigus vulgaris, pernicious anemia, rheumatic fever. Diseases tend to be specific to tissue or site where antigen is found.
Examples of type III hypersensitivity disorders
Arthus reaction (eg swelling and inflammation following tetanus vaccine), SLE, polyarteritis nodosa, poststreptococcal glomerulonephritis, serum sickness. Can be associated with vasculitis and systemic manifestations.
Examples of type IV hypersensitivity disorders
Contact dermatitis (eg poison ivy, nickel allergy), graft vs host disease, multiple sclerosis, PPD test. Response is delayed and does not involve antibodies (vs types I, II, III).
Allergic reaction to blood transfusion
It is a type I hypersensitivity reaction against plasma proteins in transfused blood. Causes urticaria, pruritus, wheezing, fever. Treat with antihistamines.
Anaphylactic reaction to blood transfusion
It is a severe allergic reaction. IgA deficient individuals must receive blood products without IgA. Causes dyspnea, bronchospasm, hypotension, respiratory arrest, shock. Treat with epinephrine.
Febrile nonhemolytic transfusion reaction
It is a type II hypersensitivity reaction. Host antibodies against donor HLA antigens and WBCs. Symptoms include fever, headaches, chills, and flushing.
Acute hemolytic transfusion rection
Type II hypersensitivity reaction. Intravesicular hemolysis (ABO blood group incompatibility) or extravascular hemolysis (host antibody reaction against foreign antigen on donor RBCs). Causes fever, hypotension, tachypnea, tachycardia, flank pain, hemoglobinuria (intravascular hemolysis), jaundice (extravascular).
Anti-ACh receptor
Myasthenia gravis
Anti-basement membrane
Goodpasture syndrome
Anticardiolipin
SLE, antiphospholipid syndrome
Lupus anticoagulant
SLE, antiphospholipid syndrome
anticentromere
Limited scleroderma (CREST syndrome-calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia)
Anti-desmosome (anti-desmoglein)
Pemphigus vulgaris
Anti-dsDNA
SLE
Anti-Smith
SLE
Anti-glutamic acid decarboxylase (GAD-65)
Type 1 diabetes mellitus
Antihemidesmosome
Bullous pemphigoid
Anti-histone
Drug-induced lupus
Anti-Jo-1
Polymyositis, dermatomyositis
Anti-SRP
Polymyositis, dermatomyositis
Anti-Mi-2
Polymyositis, dermatomyositis
Antimicrosomal
Hashimoto thyroiditis
Antithyroglobulin
Hashimoto thyroiditis
Antimitochondrial
primary biliary cirrhosis
Antinuclear antibodies
SLE, nonspecific
Antiparietal cell
pernicious anemia
Ant-Scl-70 (anti-DNA topoisomerase I)
Scleroderma (diffuse)
Anti-smooth muscle
Autoimmune hepatitis
Anti-SSA (Anti-Ro)
Sjogren syndrome
Anti-SSB (Anti-La)
Sjogren syndrome
Anti-TSH receptor
Graves disease
Anti-UI RNP (ribonucleoprotein)
Mixed connective tissue disease
IgA anti-edomysial
Celiac disease
IgA anti-tissue transglutaminase
Celiac disease
MPO-ANCA
Microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg- Strauss syndrome)
p-ANCA
Microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg- Strauss syndrome)
PR3-ANCA
Granulomatosis with polyangiitis (Wegner)
c-ANCA
Granulomatosis with polyangiitis (Wegner)
Rheumatoid factor (IgM antibody that targets IgG Fc region)
Rheumatoid arthritis
anti-CCP
Rheumatoid arthritis (more specific than rheumatoid factor)
X-linked (Burton) agammaglobulinemia
Due to a result in BTK, a tyrosine kinase gene, which causes there to be no B-cell maturation. (in Boys). Leading to recurrent bacterial and enteroviral infections after 6 months of age (due to a decrease in maternal IgG). There are absent B cells in peripheral blood, causing a decrease in Ig of all classes. There are also absent/scanty lymph nodes and tonsils.
Selective IgA deficiency
The cause is unknown. It is the most common immunodeficiency. In majority of people it is asymptomatic. It can lead to Airway and GI infections, Atopy (hyper-allergic), Anaphylaxis to IgA-containing products. There is a decrease in IgA with normal IgG, IgM levels.
Common variable immunodeficiency
Due to a defect in B-cell differentiation. There are many causes. It can be acquired in the 20’s-30’s; there is an increase risk of autoimmune disease, bronchiectasis, lymphoma, sinopulmonary infections. There are a decrease in plasma cells and Ig.
Thymic aplasia (DiGeorge syndrome)
22q11 deletion; leads to a failure to develop 3rd and 4th pharyngeal pouches, causing an absence in thymic and parthyroid glands. Patients present with tetany (hypocalcemia), recurrent viral/fungal infections (T-cell deficiency), conotruncal abnormalities (eg tetralogy of fallot, truncus arteriosus). Findings include a decrease in T cells, PTH, and Ca. There is an absent thymic shadow on CXR. 22q11 deletion detected by FISH.
IL-12 receptor deficiency
Causes a decrease Th1 response. It is autosomal recessive. It presents as disseminated mycobacterial and fungal infections; may present after administration of BCG vaccine. There will be a decrease in IFN-gamma.
Autosomal dominant hyper IgE syndrome (Job syndrome)
It is due to a deficiency of Th17 cells due to a STAT3 mutation, leading to impaired recruitment of neutrophils to sites of infection. Presentation is FATED: coarse Facies, cold (noninflamed) staphylococcal Abscesses, retained primary Teeth, increase in IgE, Dermatologic problems (eczema). Serum shows an increase in IgE and a decrease in IFN-gamma.
Chronic mucocutaneous candidiasis
Causes T-cell dysfunction. There are many causes. Presents as noninvasive Candida albicans infections of skin and mucous membranes. There are absent in vitro T-cell proliferation in response to Candida antigens. There is also an absent cutaneous reaction to Candida antigens.
Severe combined immunodeficiency
There are several types including a defect in IL-2R gamma chain (most common, X-linked) and adenosine deaminase deficiency (autosomal recessive, which leads to the accumulation of ATP and dATP. Excess dATP inhibits ribonucleotide reductase and DNA synthesis, resulting in decreased lymphocyte counts. It presents as failure to thrive, chronic diarrhea, and thrush. There are also recurrent viral, bacterial, fungal, and protozoal infections. Treatment includes bone marrow transplant (no adaptive mediated immune rejection). Lab findings will show a decrease in T-cell receptor excision circles (TRECs). There will also be an absence of a thymic shadow on CXR, germinal centers on lymph node biopsy, and T cells on flow cytometry.
Ataxia-talengiectasia
Due to a defect in ATM gene, which leads to a failure to repair double strand DNA breaks causing cell cycle arrest. It causes a triad of cerebellar defects (Ataxia), spider Angiomas (telangiectasia, and IgA deficiency. Lab findings will show an increase in alpha fetoprotein, a decrease in IgA, IgG, and IgE, lymphopenia, and cerebellar atrophy.
Hyper IgM syndrome
It is most commonly due to a defective CD40L on Th cells, which leads to defective class switching. It is x linked recessive. It presents with severe pyogenic infections early in life and opportunistic infections such as Pneumocystis, Cryptosporidium, and CMV. Lab findings will show an increase of IgM and a large decrease in IgG, IgA, and IgE.
Wiskott-Aldrich syndrome
Due to a mutation in WAS gene (x-linked recessive), which makes T cells unable to reorganize actin cytoskeleton. Presents as WATER: Wiskott-Aldrich: Thrombocytopenia, Eczema, Recurrent infections. There is also an increase risk of autoimmune disease and malignancy. Lab findings will show decrease to normal levels of IgG and IgM, an increase in IgE and IgA, and fewer and smaller platelets.
Leukocyte adhesion deficiency (type 1)
Due to a defect in LFA-1 integrin (CD18) protein on phagocytes; impaired migration and chemotaxis. It is autosomal recessive. It presents as recurrent bacterial skin and mucosal infections, absent pus formation, impaired wound healing, and delayed separation of umbilical cord (over 30 days). Lab findings will show an increase in neutrophils in serum but an absence of neutrophils at the infection sites.
Chediak-Higashi syndrome
It is due to a defect in lysosomal trafficking regulator gene (LYST), which leads to microtubule dysfunction in phagosome-lysosome fusion. It is autosomal recessive. Histology findings will show giant granules in granulocytes and platelets. There will also be pancytopenia and mild coagulation defect.
Chronic granulomatous disease
Due to a defect of NADPH oxidase, which leads to a decrease in reactive oxygen species (eg superoxide) and a decrease of respiratory burst in neutrophils. X-linked recessive is most common. It presents as an increase susceptibility to catalase positive organisms (Need PLACESS): Nocardia, Pseudomonas, Listeria, Aspergillus, Candida, E coli, S aureus, Serratia. Lab findings will show an abnormal dihydrohodamine on flow cytometry and a negative nitroblue tetrazolium dye reduction test.
Common bacterial infections in a immunodeficiencies with decrease T cells
Sepsis
Common viral infections in a immunodeficiencies with decrease T cells
CMV, EBV, JCV, VZV, chronic infection with respiratory/ GI viruses. B-cell deficiencies tend to produce recurrent bacterial infections, whereas T-cell deficiencies produce more fungal and viral infections.
Common fungal/parasites infections in a immunodeficiencies with decrease T cells
Candida (local) and Pneumcystitis pneumonia
Common bacterial infections in a immunodeficiencies with decrease B cells
Encapsulated; SHiNE SKiS: Streptococcus pneumoniae, Haemophilus influenzae type B, Neisseria emingitidis, Escherichia coli, Salmonella, Klebsiella pneumoniae, group B Strep. B-cell deficiencies tend to produce recurrent bacterial infections, whereas T-cell deficiencies produce more fungal and viral infections.
Common viral infections in a immunodeficiencies with decrease B cells
Enteroviral encephalitis, poliovirus (live vaccine contraindicated)
Common fungi/parasites infections in a immunodeficiencies with decrease B cells
GI giardiasis (no IgA)
Common bacterial infections in a immunodeficiencies with decrease granulocytes
Staphylococcus, Burkholderia cepacia, Pseudomonas aeruginosa, Serratia, Nocardia.
Common viral infections in a immunodeficiencies with decrease granulocytes
Granulocyte deficiency does not predispose patients to viral infections.
Common fungi/parasites infections in a immunodeficiencies with decrease granulocytes
Candida (systemic), Aspergillus
Common bacterial infections in a immunodeficiencies with decrease complement
Encapsulated species with early component deficiencies. Encapsulated; SHiNE SKiS: Streptococcus pneumoniae, Haemophilus influenzae type B, Neisseria emingitidis, Escherichia coli, Salmonella, Klebsiella pneumoniae, group B Strep. Neisseria with late component (MAC) deficiencies.
Common viral infections in a immunodeficiencies with decrease complement
Complement deficiency does not predispose patients to viral infections.
Common fungi/parasites infections in a immunodeficiencies with decrease complement
Complement deficiency does not predispose patients to fungi/parasites infections.
Autograft
Graft from self
Syngeneic graft (isograft)
Graft from identical twin or clone
Allograft
Graft from nonidentical individual of same species.
Xenograft
Graft from different species
Hyperacute transplant rejection
Onset is within minutes. It is due to pre-existing recipient antibodies react to donor antigen (type II hypersensitivity reaction), which activates complement. It causes widespread thrombosis of graft vessels, which causes ischemia and necrosis. The graft must be removed.
Acute transplant rejection
Onset is weeks to months. It occurs due to CD8+ T cells activated against donor MHCs and development of antibodies after the transplant (as opposed to preformed antibodies in a hyperacute rejection). It causes vasculitis of graft vessels with dense interstitial lymphocytic infiltrate. It can be prevented or reversed with immunosuppressants.
Chronic transplant rejection
Onset is months to years. It occurs due to CD4+ T cells responding to recipient APCs presenting donor peptides, including allogenic MHC. There are both cellular and humoral components. Recipient T cells react and secrete cytokines leads to proliferation of vascular smooth muscle and parenchymal fibrosis. It is dominated by arteriosclerosis.
Graft versus host disease transplant rejection
Onset varies. It occurs due to grafted immunocompetent T cells proliferating in the immunocompromised host, which reject host cells with “foreign” proteins leading to severe organ dysfunction. It causes maculopapular rash, jaundice, diarrhea, hepatosplenomegaly. It is usually due to bone marrow or liver transplants, which are rich in lymphocytes. It can potentially be beneficial in bone marrow transplant for leukemia because it can lead to a graft versus tumor effect.
Immunosuppressants
Agents that block lymphocyte activation and proliferation. They can reduce acute transplant rejection by suppressing cellular immunity. They are frequently combined to achieve efficacy with a decrease in toxicity. Chronic suppression increases the risk of infection and malignancy.
Mechanism of cyclosporine
Calcineurin inhibitor; binds cyclophilin. Blocks T-cell activation by preventing IL-2 transcription.
Use of cyclosporine
Prophylactic transplant rejection, psoriasis, and rheumatoid arthritis.
Toxicity of cyclosporin
Nephrotoxicity is the most important toxicity. Hypertension, hyperlipidemia, neurotoxicity, gingival hyperplasia, and hirsutism. Both calcineurin inhibitors are highly nephrotoxic.
Mechanism of tacrolimus (FK506)
Calcineurin inhibitor; binds FK506 binding protein (FKBP). It blocks T-cell activation by preventing IL-2 transcription.
Use of tacrolimus (FK506)
Transplant rejection prophylaxis
Toxicity of tacrolimus (FK506)
Similar to cyclosporine, there is an increase risk of diabetes and neurotoxicity; no gingival hyperplasia or hirsutism. Both calcineurin inhibitors are highly nephrotoxic.
Mechanism of sirolimus (rapamycin)
mTOR inhibitor; bindsFKBP. Blocks T-cell activation and B-cell differentiation by preventing response to IL-2.
Use of sirolimus (rapamycin)
Kidney transplant rejection prophylaxis
Toxicity of sirolimus (rapamycin)
Anemia, thrombocytopenia, leikopenia, insulin resistance, hyperlipidemia; not nephrotoxic. Kidney “sir-vives.” Synergistic with cyclosporin. Also used in drug eluting stents.
Mechanism of daclizumab
Monoclonal antibodies; block IL-2R
Use of daclizumab
Kidney transplant rejection prophylaxis
Toxicity of daclizumab
Edema, hypertension, and tremor
Mechanism of basiliximab
Monoclonal antibodies; block IL-2R
Use of basiliximab
Kidney transplant rejection prophylaxis
Toxicity of basiliximab
Edema, hypertension, and tremor
Mechanism of azathioprine
Antimetabolite precursor of 6-mercaptopurin. Inhibits lymphocyte proliferation by blocking nucleotide synthesis. Azathio-purine.
Use of azathioprine
Transplant rejection prophylaxis, rheumatoid arthritis, Crohn disease, glomerulonephritis, and other autoimmune conditions.
Toxicity of azathioprine
Leukopenia, anemia, thrombocytopenia. 6-MP degraded by xanthine oxidase; toxicity increases by allopurinol.
Mechanism of glucocorticoids
Inhibit NF-kB. Suppresses both B- and T-cell function by decreasing transcription of many cytokines.
Use of glucocorticoids
Transplant rejection prophylaxis (immunosuppression), many autoimmune disorders, inflammation.
Toxicity of glucocorticoids
Hyperglycemia, osteoporosis, central obesity, muscle breakdown, psychosis, acne, hypertension, cataracts, avascular necrosis. Can cause iatrogenic Cushing syndrome.
Aldesleukin
IL-2, used to treat renal cell carcinoma and metastatic melanoma.
Epoetin alfa
Erythropoietin, used to treat anemias (especially in renal failure).
Filgrastim
G-CSF, used for recovery of bone marrow
Sargramostim
GM-CSF, used for recovery of bone marrow
IFN-alpha
used to treat chronic hepatitis B and C, Kaposi sarcoma, and malignant melanoma.
IFN-beta
Used to treat multiple sclerosis
IFN-gamma
Used to treat chronic granulomatous disease
Romiplostim
Thrombopoietin, used to treat thrombocytopenia
Eltrombopag
Thrombopoietin, used to treat thrombocytopenia
Oprelvekin
IL-11, used to treat thrombocytopenia
Alemtuzumab
Antibody that targets CD52. Used to treat chronic lymphocytic leukemia (CLL). “Alymtuzumab”- chronic lymphocytic leukemia.
Bevacizumab
Antibody that targets VEGF. Used to treat colorectal cancer and renal cell carcinoma.
Cetuximab
Antibody that targets EGFR. Used to treat stage IV colorectal cancer and head and neck cancer.
Rituximab
Antibody that targets CD20. Used to treat B-cell non-Hodgkin lymphoma, CLL, rheumatoid arthritis, and idiopathic thrombocytopenic purpura (ITP)
Trastuzumab
Antibody that targets HER2/neu. Used to treat breast cancer. HER2- tras2zumab.
Adalimumab
Antibody that targets soluble TNF-alpha. Used to treat IBD, rheumatoid arthritis, ankylosing spondylitis, and psoriasis.
Etanercept
It is decoy TNF-alpha receptor and not monoclonal antibody.
Infliximab
Antibody that targets soluble TNF-alpha. Used to treat IBD, rheumatoid arthritis, ankylosing spondylitis, and psoriasis.
Eculizumab
Antibody that targets complement protein C5. Used to treat paroxysmal nocturnal hemoglobinuria.
Natalizumab
Antibody that targets alpha4-integrin. Used to treat multiple sclerosis and Crohn disease. α4-integrin is required for white blood cells adhesion in order to move into organs. There is a risk for progressive multifocal leukoencephalopathy (PML) in patients with JC virus.
Abciximab
Antibody that targets platelet glycoproteins IIb/IIIa. Used to treat antiplatelet agent for prevention of ischemic complications in patients undergoing percutaneous coronary intervention. IIb x IIIa equals “ab-six-imab”
Denosumab
Antibody that targets receptor activator of nuclear factor kappa-B ligand (RANKL). Used to treat osteoporosis; inhibits osteoclast maturation (mimics osteoprotegerin). DenOSumab affects OSteoclasts.
Dioxin immune Fab
Antibody that targets digoxin. Used as an antidote for digoxin toxicity.
Omalizumab
Antibody that targets IgE. Used to treat allergic asthma; prevents IgE binding to FcERI (high-affinity receptor for the Fc region of immunoglobulin E).
Palivizumab
Antibody that targets RSV F protein. Used as a RSV prophylaxis for high-risk infants. PaliVIzumab- VIrus.
Ranibizumab
Antibody that targets VEGF. Used to treat neovascular age-related macular degeneration.
