Immunology

1° membranous nephropathy

Celiac disease

Type 1 diabetes mellitus

Onset: Months to years CD4+ T cells respond to recipient APCs presenting donor peptides, including allogeneic MHC. Both cellular and humoral components (type II and IV hypersensitivity reactions). Features:- Recipient T cells react and secrete cytokines → proliferation of vascular smooth muscle, parenchymal atrophy, interstitial fibrosis. Dominated by arteriosclerosis.- Bronchiolitis obliterans (lung)- Accelerated atherosclerosis (heart)- Chronic graft nephropathy (kidney)- Vanishing bile duct syndrome (liver)

Grafted immunocompetent T cells proliferate in the immunocompromised host and reject host cells with "foreign" proteins → severe organ dysfunction. Type IV hypersensitivity reaction. Features:- Maculopapular rash, jaundice, diarrhea, hepatosplenomegaly- Usually in bone marrow and liver transplants (rich in lymphocytes)- Potentially beneficial in bone marrow transplant for leukemia (graft-versus-tumor effect)

A 2° lymphoid organ that has many afferents, 1 or more efferents. Encapsulated, with trabeculae. Functions are nonspecific filtration by macropahges, storage of B and T cells, and immune response activation. Follicle: Site of B-cell localization and proliferation. In outer cortex. 1° follicles are dense and dormant. 2° follicles have pale central germinal centers and are active. Medulla: Consists of medullary cords (closely packed lymphocytes and plasma cells) and medullary sinuses. Medullary sinuses communicate with efferent lymphatics and contain reticular cells and macrophages. Paracortex: 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 devloped in patients with DiGeorge syndrome.Paracortex enlarges in extreme cellular immune respones (eg, viral infection).

Cervical: Head and neck Mediastinal: Trachea and esophagusHilar: Lungs Axillary: Upper limb, breast, skin above umbilicus Celiac: Liver, stomach, spleen, pancreas, upper duodenumSuperior mesenteric: Lower duodenum, jejunum, ileum, colon to splenic flexureInferior mesenteric: Colon from splenic flexure to upper rectum Para-aortic: Testes, ovaries, kidneys, uterus Internal iliac: Lower rectum to anal canal (above pectinate line), bladder, vagina (middle third), cervix, prostate Superficial inguinal: Anal canal (below pectinate line), skin below umbilicus, scrotum, vulva

Located in LUQ of abdomen, anterior to left kidney, protected by 9th-11th ribs. Sinusoids are 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.- B cell are found in follicles within the white pulp.- The marginal zone, in between the red pulp and white pulp, contains macrophages and specialized B cells, and is where antigen-presenting cells (APCs) capture blood-borne antigens for recognition by lymphocytes. Splenic macrophages remove encapsulated bacteria. Splenic dysfunction (eg, postsplenectomy state in sickle cell disease): ↓ IgM → ↓ complement activation → ↓ C3b opsonization → ↑ susceptibility to encapsulated organisms.Postsplenectomy blood findings:- Howell-Jolly bodies (nuclear remnants)- Target cells- Thrombocytosis (loss of sequestration and removal)- Lymphocytosis (loss of sequestration)Vaccinate patients undergoing splenectomy against encapsulated organisms (pneumococcal, Hib, meningococcal).

Located in the anteriorsuperior mediastinum. Site of T-cell differentiation and maturation.- Encapsulated.- 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 Hassal corpuscles containing epithelial reticular cells. Normal neonatal thymus "sail-shaped" on CXR, involutes with age. Hypoplastic in DiGeorge syndrome and severe combined immunodeficiency (SCID). Thymoma – neoplasm of thymus. Associated with myasthenia gravis and superior cava syndrome.

Innate immunity:- Components: Neutrophils, macrophages, monocytes, dendritic cells, natural killer (NK) cells (lymphoid origin), complement, physical epithelial barriers, secreted enzymes.- Mechanism: Germline encoded- Resistance: Resistance persists through generations; does not change within organism's lifetime- Response to pathogens: Nonspecific, occurs rapidly (minutes to hours), no memory response- Secreted proteins: Lysozyme, complement, C-reactive protein (CRP), defensins- Key features in pathogen recognition: Toll-like receptors (TLR): pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) and lead to activation of NF-κB. Examples of PAMPs include LPS (gram ⊝ bacteria), flagellin (bacteria), nucleic acids (viruses). Adaptive immunity:- Components: T cells, B cells, circulating antibodies- Mechanism: Variation through V(D)J recombination during lymphocyte development- Resistance: Microbial resistance not heritable- Response to pathogens: Highly specific, refined over time, develops over long periods; memory response is faster and more robust- Secreted proteins: Immunoglobulins- Key features in pathogen recognition: Memory cells: activated B and T cells; subsequent exposure to a previously encountered antigen → stronger, quicker immuen response.

Lymphocyte member of innate immune system. - Use perforin and granzymes to induce apoptosis of virally infected cells and tumor cells. - Also kills via antigen-dependent cell-mediated cytotoxicity (CD16 binds Fc region of bound Ig, activating the NK cell). Activity enhanced by IL-2, IL-12, IFN-α, and IFN-β. Induced to kill when exposed to a nonspecific activation signal on target cell and/or to an absence of MHC I on target cell surface.

B cells: Humoral immunityRecognize antigen – undergo somatic hypermutation to optimize antigen specificity.Produce antibody – differentiate into plasma cells to secrete specific immunoglobulins.Maintain immunologic memory – memory B cells persist and accelerate future response to antigen. T cells: Cell-mediated immunity.CD4+ T cells help B cell make antibodies and produce cytokines to recruit phagocytes and activate other leukocytes.CD8+ T cell directly kill virus-infected cells.Delayed cell-mediated hypersensitivity (type IV).Acute and chronic cellular organ rejection.

Positive selection: Thymic cortex. T cells expressing TCRs capable of binding self-MHC on cortical epithelial cells survive. Negative selection: Thymic medulla. T cells expressing TCRs with high affinity for self antigens undergo apoptosis or become regulatory T cells. Tissue-restricted self-antigens are expressed in the thymus due to the action of autoimmune regulator (AIRE); deficiency leads to autoimmune polyendocrine syndrome-1. Lymph node:Helper T cell → IL-12, IFN-γ → Th1Helper T cell → IL-2, IL-4 → Th2Helper T cell → TGF-β, IL-6 → Th17Heper T cell → TGF-β → Treg

Secretes: IFN-γ  Function: Activates macrophages and cytotoxic T cells to kill phagocytosed microbes. Induced by: IFN-γ, IL-12Inhibited by: IL-4, IL-10 (from Th2 cell) Immunodeficiency: Mendelian susceptibility to mycobacterial disease.

Secretes: IL-4, IL-5, IL-6, IL-10, IL-13 Function: Activate eosinophils and promote production of IgE for parasite defense Induced by: IL-2, IL-10Inhibited by: IFN-γ (from Th1 cell)

Secretes: IL-17, IL-21, IL-22 Function: Immunity against extracellular microbes, through induction of neutrophilic inflammation. Induced by: TGF-β, IL-1, IL-6Inhibited by: IFN-γ, IL-4 Immunodeficiency: Hyper-IgE syndrome

Secretes: TGF-β, IL-10, IL-35 Function: Prevent autoimmunity by maintaining tolerance to self-antigens.Identified by expression of CD3, CD4, CD25, FOXP3. Induced by: TGF-β, IL-2Inhibited by: IL-6 Immunodeficiency: IPEX (Immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome – genetic deficiency of FOXP3 → autoimmunity. Characterized by enteropathy, endocrinopathy, nail dystrophy, dermatitis, and/or other autoimmune dermatologic conditions. Associated with diabetes in male infants.

Th1 cells secrete IFN-γ, which enhances the ability of monocytes and macrophages to kill microbes they ingest. This function is also enhanced by interaction of T cell CD40L with CD40 on macrophages.

Kill virus-infected, neoplastic, and donor graft cells by inducing apoptosis. Release cytotoxic granules containing preformed proteins (eg, perforin, granzyme B). Cytotoxic T cells have CD8, which binds to MHC I on virus-infected cells.

APCs: B cells, dendritic cells, Langerhans cells, macrophages.Two signals are required for T-cell activation, B-cell activation, and class switching. T-cell activation:1. Dendritic cell (specialized APC) samples antigen, processes antigen, and migrates to the draining lymph node.2. T-cell activation (signal 1): antigen is presented as MHC II and recognized by TCR on Th (CD4+) cell. Endogenous or cross-presented antigen is presented on MHC I to Tc (CD8+) cell.3. Proliferation and survival (signal 2): costimulatory signal via interaction of B7 (CD80/86) on dendritic cell and CD28 on naïve T cell.4. Th cell activates and produces cytokines. Tc cell activates and is able to recognize and kill virus-infected cell. B-cell activation and class switching:1. 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.3. CD40 receptor on B cell binds CD40L on Th cell.4. Th cell secretes cytokines that determine Ig class switching of B cell. B cell activates and undergoes class switching, affinity maturation, and antibody production.

Fab (containing the variable/hypervariable) regions 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: Fragment, antigen binding- Determines idiotype: unique antigen-binding pocket, only 1 antigenic specificity expressed per B cell Fc: Constant - Carboxy terminal- Complement binding (CH2)- Macrophage binding (CH2 and CH3)- Carbohydrate side chains- Determines isotype (IgM, IgD, etc) Generation of antibody diversity (antigen independent)1. Random recombination of VJ (light-chain) or V(D)J (heavy-chain) genes2. Random addition of nucleotides to DNA during recombination by terminal deoxynucleotidyl transferase (TdT)3. Random combination of heavy chains with light chains.  Generation of antibody specificity (antigen dependent)4. Somatic hypermutation and affinity maturation (variable region)5. Isotype switching (constant region)

All isotypes can exist as monomers. Mature, naive B cells prior to activation express IgM and IgD on their surfaces. They may differentiate in germinal centers of lymph nodes by isotype switching (gene rearrangement; induced by cytokines and CD40L) into plasma cells that secrete IgA, IgE, or IgG. IgG: Main antibody in 2° response to an antigen. Most abundant isotype in serum. Fixes complement, opsonized bacteria, neutralizes bacterial toxins and viruses. Only isotype that crosses the placenta (provides infants with passive immunity). IgA: Prevents attachment of bacteria and viruses to mucous membranes; does not fix complement. Monomer (in circulation) or dimer (with J chain 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 lower serum concentrations. Released into secretions (tears, saliva, mucus) and breast milk. Picks up secretory component from epithelial cells, which protects the Fc portion from luminal proteases. IgM: Produced in the 1° (immediate) response to an antigen. Fixes complement. Cannot cross the placenta. Antigen receptor on the surface of B cells. Monomer on B cell, pentamer with J chain when secreted. Pentamer enables avid binding to antigen while humoral response evolves. IgD: Unclear function. Found on surface of many B cells an in serum. IgE: Binds mast cells and basophils; cross-links when exposed to allergen, mediating immediate (type I) hypersensitivity through release of inflammatory mediators such as histamine. Contributes to immunity to parasites by activating eosinophils. Lowest concentration in serum.

Thymus-independent antigens: Antigens lacking a peptide component (eg, lipopolysaccharides from gram ⊝ bacteria); cannot be presented by MHC to T cells. Weakly 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.

System of hepatically synthesized plasma proteins that play a role in innate immunity and inflammation. Membrane attack complex (MAC) defends against gram ⊝ bacteria. Activation pathways:- Classic – IgG or IgM mediated.- Alternative – microbe surface molecules.- Lectin – mannose or other surgars on microbe surface. Functions:- C3b – opsonization- C3a, C4a, C5a – anaphylaxis- C5a – neutrophil chemotaxis- C5b-9 – cytolysis by MAC Opsonins – C3b and IgG are the two 1° opsonins in bacterial defense; enhance phagocytosis. C3b also helps clear immune complexes.Inhibitors – decay-accelerating factor (DAF, aka CD55) and C1 esterase inhibitor help prevent complement activation of self cells (eg, RBCs).

Interleukin-2: Stimualtes growth of helper, cytotoxic, and regulatory T cells, and NK cells. Interleukin-3: Supports growth and differentiation of bone marrow stem cells. Functions like GM-CSF.

Involves the activation of the phagocyte NADPH oxidase complex (eg, in neutrophils, monocytes), which utilizes O2 as a substrate.Plays and important role in the immune response → rapid release of reactive oxygen species (ROS). - NADPH plays a role in both the creation and neutralization of ROS. - Myeloperoxidase contains a blue-green heme-containing pigment that gives sputum its color. Phagocytes of patients with CGD lack superoxide dismutase and cannot make H2O2 from O2. They can utilize H2O2 generated by invading organisms and convert it to ROS. Patients are at ↑ risk for infection by catalase ⊕ species (eg, S aureus, Aspergillus) capable of neutralizing their own H2O2, leaving phagocytes without ROS for fighting infections. Pyocyanin of P aeruginosa generates ROS to kill competing pathogens. Oxidative bust also leads to K+ influx, which releases lysosymal enzymes from proteoglycans. Lactoferrin is a protein found in secretory fluids and neutrophils that inhibits microbial growth via iron chelation.

A part of innate host defense against both RNA and DNA viruses.  Interferons are glycoproteins synthesized by virus-infected cells that act on local cells, "priming" them for viral defense by downregulating protein synthesis to resist potential viral replication and upregulating MHC expression to facilitate recognition of infected cells.

T cells: - TCR (binds antigen-MHC complex)- CD3 (associated with TCR for signal transduction)- CD28 (binds B7 on APC) Helper T cells: CD4, CD40L, CXCR4/CCR5Cytotoxic T cells: CD8Regulatory T cells: CD4, CD25 B cells:- Ig (binds antigen)- CD19, CD20, CD21 (receptor for EBV), CD40- MHC II, B7 Macrophages:- CD14 (receptor for PAMPs, eg, LPS), CD40- CCR5- MHC II, B7 (CD80/86)- Fc and C3b receptors (enhanced phagocytosis) NK cells: CD16, CD56  Hematopoietic stem cells: CD34

- MMRV- Yellow virus- BCG- Influenza (nasal)- Polio (sabin)- Rotavirus- Adenovirus (nonattenuated, given to military recruits)- Smallpox Microorganism loses its pathogenicity but retains capacity for transient growth within inoculated host. Induces cellular and humoral responses.MMR and varicella vaccines can be given to HIV ⊕ patients without evidence of immunity if CD4 cell count ≥200 cells/mm3.- Often contraindicated in pregnancy and immunodeficiency.

- Rabies- Influenza (injected)- Polio (salk) (k for killed)- Hepatitis A Pathogen is inactivated by heat or chemicles. Maintaining epitope structure on surface antigens is important for immune response. Mainly induces a humoral response.

- Hepatitis B (HbsAg)- HPV (types 6, 11, 16, and 18)- Acellular pertussis (aP)- Neisseria meningitidis (various strains)- Streptococcus pneumoniae- Haemophilus influenzae type b Includes only the antigens that best stimulate the immune system. Virus-like particles are multiprotein structures that illicit a strong B- and T-cell response but contain no viral genetic material, so they are not infectious. They are used in the hepatitis B and HPV vaccines.

- Clostridium tetani- Corynebacterium diphtheriae Denatured bacterial toxin with an intact receptor binding site. Stimulates the immune system to make antibodies without potential for causing disease. Antitoxin levels decrease with time, may require booster.

Anaphylactic and atopic – two phases:- Immediate (minutes): antigen crosslinks preformed IgE on presensitized mast cells → immediate degranulation → release of histamine (a vasoactive amine) and tryptase (a marker of mast cell activation).- Late (hours): chemokines (attract inflammatory cells, eg, eosinophils) and cytokines (eg, leukotriens) from mast cells → inflammation and tissue damage. Test: skin test or blood test (ELISA) for allergen-specific IgE. Example:- Anaphylaxis (eg, food, drug, or bee sting allergies)

Antibodies bind to cell-surface antigens → cellular destruction, inflammation, and cellular dysfunction.Direct Coombs test – detects antibodies attached directly to the RBC surface.Indirect Coombs test – detecs presence of unbound antibodies in the serum. Cellular destruction – cell is opsonized (coated) by antibodies, leading to either:- Phagocytosis and/or activation of complement system.- NK cell killing (antibody-dependent cellular cytotoxicity).Examles:- Autoimmune-hemolytic anemia- Immune thrombocytopenia- Transfusion reactions- Hemolytic disease of the newborn Inflammation – binding of antibodies to cell surfaces → activation of complement system and Fc receptor-mediated inflammation- Goodpasture syndrome- Rheumatic fever- Hyperacute transplant rejection Cellular dysfunction – antibodies bind to cell surface receptors → abnormal blockade or activation of downstream process- Myasthenia gravis- Graves disease- Pemphigus vulgaris

Immune complex–antigen-antibody (mostly IgG) complexes activate complement, which attracts neutrophils; neutrophils release lysosomal enzymes.- Can be associated with vasculitis and systemic manifestations. Examples:- SLE- Polyarteritis nodosa- Poststreptococcal glomerulonephritis Serum sickness – the prototype immune complex disease. Antibodies to foreign proteins are produced and 1-2 weeks later, antibody-antigen complexes form and deposit in tissues → complement activation → inflammation and tissue damage.- Fever, urticaria, arthralgia, proteinuria, lymphadenopathy occur 1-2 weeks after antigen exposure. Serum sickness-like reactions are associated with some drugs (may act as haptens, eg, penicillin) and infections (eg, hepatitis B). Arthus reaction – a local subacute immune complex-mediated hypersensitivity reaction. Intradermal injection of antigen into a presensitized (has circulating IgG) individual leads to immune complex formation in the skin. Characterized by edema, necrosis, and activation of complement.

Two mechanisms, each involving T cells:1. Direct cell cytotoxicity: CD8+ cytotoxic T cell kill targeted cells.2. Inflammatory reaction: effector CD4+ T cells recognize antigen and release inflammation-inducing cytokines. Response does not infolve antibodies. Examples:- Contact dermatitis (eg, poison ivy, nickel allergy)- Graft-versus-host disease- Erythema nodosum Tests: - PPD (tuberculosis infection)- Patch test (cause of contact dermatitis)- Candida extract (T cell immune funtion)

Allergic/anaphylactic reaction: Type I hypersensitivity reaction against plama proteins in transfused blood. IgA-deficient individuals must receive blood products without IgA.- Urticaria, pruritus, fever, wheezing, hypotension, respiratory arrest, shock- Within minutes to 2-3 hours Febrile nonhemolytic transfusion reaction: Two known mechanisms: type II hypersensitivity reaction with host antibodies against donor HLA and WBCs; and induced by cytokines that are created and accumulate during the storage of blood products.- Fever, headaches, chills, flushing- Within 1-6 hours Acute hemolytic transfusion reaction: Type II hypersensitivity reaction. Intravascular hemolysis (ABO blood group incompatibility) or extravascular hemolysis (host antibody reaction against foreign antigen on donor RBCs).- Fever, hypotension, tachypnea, tachycardia, flank pain, hemoglobinuria (intravascular hemolysis), jaundice (extravascular)- Within 1 hour Transfusion-related acute lung injury: Donor anti-leukocyte antibodies against recipient neutrophils and pulmonary endothelial cells.- Respiratory distress and noncardiogenic pulmonary edema- Within 6 hours

Hyperacute: within minutes- Pre-existing recipient antibodies react to donor antigen (type II hypersensitivity reaction), activate complement- Widespread thrombosis of graft vessels → ischemia/necrosis- Graft must be removed Acute: weeks to months- Cellular: CD8+ T cells and/or CD4+ T cells activated against donor MHC (type IV hypersensitivity reaction)- Humoral: similar to hyperacute, except antibodies develop after transplant- Vasculitis of graft vessels with dense interstitial lymphocytic infiltrate. Prevent/reverse with immunosuppressants. Chronic: months to years- CD4+ T cells respond to recipient APCs presenting donor peptides, including allogeneic MHC.- Both cellular and humoral components (type II and IV hypersensitivity reactions)- Recipient T cells react and secrete cytokines → proliferation of vascular smooth muscle, parenchymal atrophy, interstitial fibrosis. Dominated by arteriolosclerosis.- Organ-specific examples: Bronchiolitis obliterans (lung), accelerated atherosclerosis (heart), chronic graft nephropathy (kidney), vanishing bile duct syndrome (liver) Graft-versus-host disease:- Grafted immunocompetent T cells proliferate in the immunocompromised host and reject host cells with "foreign" proteins → severe organ dysfunction. Type IV hypersensitivity reaction.- Maculopapular rash, jaundice, diarrhea, hepatosplenomegaly. Usually in bone marrow and liver transplants (rich in lymphocytes). Potentially beneficial in bone marrow transplant for leukemia (graft-versus-tumor effect).

↓ T-cells:- Bacteria: Sepsis- Viruses: CMV, EBV, JC virus, VZV, chronic infeciton with respiratory/GI viruses- Fungi/parasites: Superficial, local Candida, PCP, Cryptococcus ↓ B-cells:- Bacteria: Encapsulated (Pseudomonas, Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis, E coli, Salmonella, Klebsiella pneumoniae, group B Streptococcus)- Viruses: Enteroviral encephalitis, poliovirus (live vaccine contraindicated)- Fungi/parasites: GI giardiasis (no IgA) ↓ Granulocytes:- Bacteria: Staphylococcus, Burkholderia, Pseudomonas, Serratia, Nocardia- Viruses: N/A- Fungi/parasites: Systemic Candida, Aspergillus, Mucor

Clonal mast cell proliferation occurs in the bone marrow, skin, and other organs.- Often associated with mutations in the KIT receptor tyrosine kinase.- Cells characterized by prominent expression of mast cell tryptase. Excessive histamine release mediates syncope, flushing, hypotension, pruritus, urticaria. In addition, histamine induces gastric acid secretion, which can lead to gastric ulceration. The excess acid also inactivates pancreatic intestinal enzymes, causing diarrhea.