Immune System: Organs and Functions

• Immune system organs are split into primary and secondary.

Primary Organs

• Bone marrow handles immune cell production and B cell maturation.
• The thymus handles T cell maturation.

Secondary Organs

• Spleen, lymph nodes, tonsils, adenoids, appendix, and Peyer patches.
• Allow immune cells to interact with antigens.

Lymph Nodes

• A secondary lymphoid organ with many afferents, and at least one efferent.
• Encapsulated, containing trabeculae.
• Functions: nonspecific filtration by macrophages, circulation of B and T cells, and immune response activation.

Follicle

• Located in the outer cortex of lymph nodes.
• Site of B-cell localization and proliferation.
• Primary follicles are dense and quiescent.
• Secondary follicles have pale central germinal centers, and are active.

Medulla

• Consists of medullary cords with closely packed lymphocytes and plasma cells, and medullary sinuses.
• Medullary sinuses contain reticular cells and macrophages, and communicate with efferent lymphatics.

Paracortex

• Contains T cells, and is located in the cortex between follicles and medulla.
• Contains high endothelial venules where T and B cells enter from the blood.
• Underdeveloped in those with DiGeorge syndrome.
• Enlarges in an extreme cellular immune response causing paracortical hyperplasia and then lymphadenopathy.

Lymphatic Drainage Associations

• Submandibular and submental nodes drain the oral cavity, anterior tongue, and lower lip.
• Deep cervical nodes drain the head, neck, and oropharynx.
• Supraclavicular nodes drain the right hemithorax (right) or the left hemithorax, abdomen, and pelvis (left Virchow node).
• Mediastinal nodes drain the trachea and esophagus.
• Hilar nodes drain the lungs.
• Axillary nodes drain the upper limb, breast, and skin above the umbilicus.
• Epitrochlear nodes drain the hand and forearm.
• Celiac nodes drain the liver, stomach, spleen, pancreas, and upper duodenum.
• Superior mesenteric nodes drain the lower duodenum, jejunum, ileum, and colon to splenic flexure.
• Inferior mesenteric nodes drain the colon from splenic flexure to the upper rectum.
• Periumbilical nodes drain the abdomen and pelvis.
• Para-aortic nodes drain the pair of testes, ovaries, kidneys, fallopian tubes, and fundus of the uterus.
• External iliac nodes drain the body of the uterus, cervix, and superior bladder.
• Internal iliac nodes drain the cervix, proximal vagina, corpus cavernosum, prostate, inferior bladder, and lower rectum to the anal canal (above pectinate line).
• Superficial inguinal nodes drain the distal vagina, vulva, scrotum, urethra, anal canal (below pectinate line), and skin below the umbilicus (except popliteal area).
• Popliteal nodes drain the dorsolateral foot and posterior calf.

Lymphatic Ducts

• The right lymphatic duct drains the right side of the body above the diaphragm into the junction of the right subclavian and internal jugular vein.
• The thoracic duct drains below the diaphragm and left thorax and upper limb into junction of left subclavian and internal jugular veins; rupture of the thoracic duct can cause chylothorax.

Spleen

• Located in the LUQ of abdomen, anterolateral to left kidney, protected by 9th-11th ribs.
• Splenic dysfunction leads to decreased IgM and complement activation, increasing susceptibility to encapsulated organisms.
• Postsplenectomy findings: Howell-Jolly bodies, target cells, thrombocytosis, and lymphocytosis.
• Patients undergoing splenectomy or with splenic dysfunction should be vaccinated against encapsulated organisms.

Periarteriolar Lymphatic Sheath

• Contains T cells.
• Located within white pulp of the spleen.

Follicle - Spleen

• Contains B cells, located within white pulp.

Marginal Zone

• Contains macrophages and specialized B cells.
• Site where antigen-presenting cells capture blood-borne antigens for recognition by lymphocytes.
• Located between red pulp and white pulp.

Thymus

• Located in the anterosuperior mediastinum.
• Site of T-cell differentiation and maturation, and is encapsulated.
• The thymus epithelium originates in the 3rd pharyngeal pouch, and thymic lymphocytes are of mesodermal origin.
• The cortex is dense with immature T cells, and the medulla is pale with mature T cells and Hassall corpuscles.
• The normal neonatal thymus is "sail-shaped" on CXR, and involutes by age 3 years.
• Absent thymic shadow or hypoplastic thymus is seen in some immunodeficiencies.
• Thymoma is a neoplasm of the thymus, and can be associated with myasthenia gravis, superior vena cava syndrome, pure red cell aplasia, and Good syndrome.

Innate immunity components

• Neutrophils, macrophages, monocytes, dendritic cells, natural killer (NK) cells, complement, physical epithelial barriers, secreted enzymes.
• Mechanism: germline encoded.
• Response to pathogens: nonspecific, rapid, no memory response.
• Secreted proteins: lysozyme, complement, CRP, defensins, cytokines.

Adaptive immunity components

• Key features in pathogen recognition: Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and lead to activation of NF-κB.
• T cells, B cells, circulating antibodies.
• Variation through V(D)J recombination during lymphocyte development.
• Response to pathogens: highly specific, refined over time and develops over long periods; memory response is faster and more robust.
• Secreted proteins: immunoglobulins, cytokines.
• Memory cells: activated B and T cells; subsequent exposure to a previously encountered antigen leads to a stronger, quicker immune response.
• Adaptive immune responses decrease with age.

Immune Privilege

• Organs and tissues where chemical or physical mechanisms limit immune responses to foreign antigens to avoid damage from inflammatory sequelae.
• Allograft rejection at these sites is less likely.

Major Histocompatibility Complex I - MHC I

• Encoded by HLA genes.
• Present antigen fragments to T cells and bind T-cell receptors.
• Loci: HLA-A, HLA-B, HLA-C (one letter).
• Binds TCR and CD8, consists of one long and one short chain.
• Expression: all nucleated cells, APCs, and platelets (except RBCs).
• Function: presents endogenous antigens to CD8+ cytotoxic T cells.
• Antigen loading: antigen peptides loaded onto MHC I in RER after delivery via TAP.
• Associated protein: β2-microglobulin.

Major Histocompatibility Complex II - MHC II

• Loci: HLA-DP, HLA-DQ, HLA-DR (two letters).
• Binds TCR and CD4 and has 2 equal-length chains.
• Expression: on all APCs.
• Function: presents exogenous antigens to CD4+ helper T cells.
• Antigen loading: antigen loaded following release of invariant chain in an acidified endosome.

HLA Subtypes Associated with Diseases

• B27 with Psoriatic arthritis, Ankylosing spondylitis, IBD-associated arthritis, Reactive arthritis.
• B57 with Abacavir hypersensitivity.
• DQ2/DQ8 with Celiac disease.
• DR3 with DM type 1, SLE, Graves disease, Hashimoto thyroiditis, and Addison disease.
• DR4 with Rheumatoid arthritis, DM type 1, and Addison disease.

Functions of Natural Killer Cells

• Lymphocyte member of the innate immune system.
• Uses perforin and granzymes to induce apoptosis of virally infected cells and tumor cells.
• Activity enhanced by IL-2, IL-12, IFN-α, and IFN-β.
• Induced to kill when exposed to a nonspecific activation signal on a target cell and/or to an absence of an inhibitory signal like MHC I on target cell surface.
• Also kills with antibody-dependent cell-mediated cytotoxicity.

Major functions of B cells

• Humoral immunity.
• Recognize and present antigen and undergo somatic hypermutation to optimize antigen specificity.
• Produce antibodies; differentiate into plasma cells to secrete specific immunoglobulins.
• Maintain immunologic memory with memory B cells persisting and accelerating future response to antigen.

Major functions of T cells

• Cell-mediated immunity.
• 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 and tumor cells via perforin and granzymes.
• Involved in type IV hypersensitivity reactions, also causes acute and chronic cellular organ rejection.

Positive Selection

• Thymic cortex.
• Keeps T cells that recognize self-peptides to allow for cooperation in immune responses.
• Double positive thymocytes expressing TCRs that recognize self-peptide MHC complexes receive a survival signal.

Negative Selection

• Thymic medulla.
• Removes T cells that bind too strongly to self-peptides.
• Thymocytes expressing TCRs with high affinity for self antigens undergo apoptosis or become regulatory T cells.
• Autoimmune regulator AIRE protein drives negative selection, and deficiency leads to autoimmune polyendocrine syndrome.

Macrophage-Lymphocyte Interaction

• Th1 cells secrete IFN-γ, enhancing ability of monocytes and macrophages to kill microbes they ingest.
• This function is enhanced by the interaction of T cell CD40L with CD40 on macrophages.
• Macrophages also activate lymphocytes via antigen presentation.

Cytotoxic T cells

• Kill virus-infected, neoplastic, and donor graft cells by inducing apoptosis.
• Release cytotoxic granules containing preformed proteins and have CD8.
• CD8 is bound to the MHC I found on virus-infected cells.

Regulatory T cells

• Help maintain specific immune tolerance by suppressing CD4+ and CD8+ T-cell effector functions.
• Identified by expression of CD3, CD4, CD25, and FOXP3.
• Activated regulatory T cells produce anti-inflammatory cytokines.

IPEX Syndrome

• Genetic deficiency of FOXP3 leads to autoimmunity.
• Characterized by enteropathy, endocrinopathy, nail dystrophy, dermatitis, and/or other autoimmune dermatologic conditions.
• Associated with diabetes in male infants.

T-cell activation

• APC ingests and processes antigen, migrating to the draining lymph node.
• T-cell activation (signal 1) occurs when exogenous antigen is presented on MHC II and recognized by TCR on Th cell or endogenous or cross-presented antigen is presented on MHC I to Tc cell.
• Proliferation and survival (signal 2) occurs via costimulatory signal, B7 protein on dendritic cell interacts with CD28 on naïve T cell.
• Activated Th cell produces cytokines, and Tc cell recognizes and kills virus-infected cell.

B-cell activation and Class Switching

• Th-cell activation occurs as above.
• B-cell receptor-mediated endocytosis occurs.
• Exogenous antigen is presented on MHC II and recognized by TCR on Th cell.
• CD40 receptor on B cell binds CD40 ligand on Th cell.
• Th cells secrete cytokines to determine Ig class switching, activating B cells to produce IgM and undergo class switching and affinity maturation.

Antibody Structure and Function

• Fab fragment contains light and heavy chains and recognizes antigens.
• The Fc region of IgM and IgG fixes complement; Heavy chain contributes to Fc and Fab regions, whereas light chain contributes only to Fab region.
• Fab determines the idiotype- the unique antigen binding pocket; only 1 antigenic specificity expressed per B cell.
• Fc confers the isotype and binds complement.

Generation of Antibody Diversity - Antigen Independent

• Random recombination of VJ light-chain or VDJ heavy-chain genes by RAG1 and RAG2.
• Random addition of nucleotides to DNA during recombination by terminal deoxynucleotidyl transferase.
• Random combination of heavy chains with light chains.

Generation of Antibody Specificity - Antigen Dependent

• Somatic hypermutation and affinity maturation, and isotype switching.

Immunoglobulin Isotypes

• All isotypes exists as monomers.
• Mature, naïve B cells prior to activation express IgM and IgD on their surfaces.
• They may differentiate in germinal centers of lymph nodes by isotype switching into plasma cells that secrete IgA, IgG, or IgE.
• Affinity refers to the individual antibody-antigen interaction, while avidity describes the cumulative binding strength of all antibody-antigen interactions in a multivalent molecule.

IgG

• Has Greets the Growing fetus, associated with warm autoimmune hemolytic anemia, the main antibody in 2° response to an antigen, most abundant isotype in serum, fixes complement, opsonizes bacteria, and neutralizes bacterial toxins and viruses.

IgA

• Prevents attachment of bacteria and viruses to mucous membranes and is a monomer/dimer that crosses epithelial cells by transcytosis.
• Most produced antibody overall, but has lower serum concentrations. Released into secretions and breast milk.

IgM

• First antibody produced during an immune response.
• It fixes complement, serving as an antigen receptor on the surface of B cells that are monomer on B cell, pentamer with J chain when secreted.
• Enables avid binding to antigen while humoral response evolves and being associated with cold autoimmune hemolytic anemia.

IgD

• Expressed on the surface of mature, naïve B cells and normally has low levels detectable in serum.

IgE

• Binds mast cells and basophils, cross-links when exposed to allergen, mediating immediate hypersensitivity through release of inflammatory mediators such as histamine and contributing to immunity to parasites by activating eosinophils.

Thymus-independent Antigens

• Antigens lacking a peptide component and is not presented by MHC to T cells.
• Vaccines often require boosters and adjuvants.

Thymus-dependent Antigens

• Antigens containing a protein component.
• Class switching and immunologic memory occur with direct contact of B cells with Th cells.

Complement

• System of hepatically synthesized plasma proteins involved in innate immunity and inflammation with membrane attack complex MAC defends against gram bacteria.
• Classic - IgG or IgM mediated.
• Alternative - microbe surface molecules.
• Lectin - mannose or other sugars on microbe surface.

Functions

• C3b which causes opsonization, C3a, C4a, and C5a which causes anaphylaxis, C5a causes neutrophil chemotaxis, and C5b-9 which causes cytolysis.
• Opsonins include C3b and IgG, are the top opsonins in bacterial defense, enhancing phagocytosis and also helping clear immune complexes.
• Inhibitors include decay-accelerating factor DAF also called CD55, and C1 esterase inhibitor, which helps prevent complement activation on self cells.

Complement Protein Deficiencies

• Early complement deficiencies increase the risk of severe, recurrent pyogenic sinus and respiratory tract infections and of SLE.
• Terminal complement deficiencies increase susceptibility to recurrent Neisseria bacteremia.

Complement Regulatory Protein Deficiencies

• The C1 esterase inhibitor deficiency causes hereditary angioedema and high bradykinin and the Paroxysmal nocturnal hemoglobinuria.
• CDH is caused by a defect in the PIGA genethat that prevents the formation of glycosylphosphatidylinositol GPI anchors for complement inhibitors, causing complement-mediated intravascular hemolysis and atypical venous thrombosis.

Important Cytokines

• Acute (IL-1, IL-6, TNF-α), then recruit (IL-8, IL-12).
• IL-1 causes fever, acute inflammation, activates endothelium, and induces chemokine secretion
• IL-6 causes fever and stimulates production of acute-phase proteins, and IL-8 is a major chemotactic factor for neutrophils.
• IL-12 induces differentiation of T cells into Th1 cells and activates NK cells.
• IL-2 stimulates growth of helper, cytotoxic, and regulatory T cells, and NK cells; also IL-3 supports growth and differentiation of bone marrow stem cells.
• IFN-γ stimulates macrophages to kill phagocytosed pathogens, activates macrophages to induce granuloma formation, and increases MHC expression and antigen presentation by all cells.
• IL-4 promotes growth of B cells, enhances class switching to IgE and IgG, and induces differentiation of T cells into Th2 cells.
• IL-5 promotes growth and differentiation of B cellsenhances class switching to IgA and stimulates growth and differentiation of Eosinophils.
• IL-10 attenuates inflammatory response, and decreases expression of MHC class II and Th1 cytokines. - IL-13 promotes IgE production by B cells and induces alternative macrophage activation.

Respiratory Burst

• Also called oxidative burst that involves the activation of the phagocyte NADPH oxidase complex, utilizing O2 as a substrate and playing an important role in the immune response.
• NADPH plays a role in both the creation and neutralization of reactive oxygen species.
• Myeloperoxidase contains a blue-green, heme-containing pigment that gives sputum its color.
• Phagocytes of patients with CGD can utilize H2O2 generated by invading organisms and convert it to ROS, increasing risk for catalase positive infection species.

Interferons

• A part of innate host defense that synthesize glycoprotein primed cells to resist viral replication and play a major role in activating anti tumor immunity.

Mechanism

• Cells infected with a virus synthesize these glycoproteins, which act on local cells, priming them for viral defense by downregulating protein synthesis to resist potential viral replication and by upregulating MHC expression to facilitate recognition of infected cells.

Use

• It is used to treat chronic HBV, Kaposi sarcoma, hairy cell leukemia, renal cell carcinoma, malignant melanoma, multiple sclerosis, and chronic granulomatous disease.
• The adverse effects are Flulike symptoms, depression, neutropenia, myopathy, and interferon-induced autoimmunity.

Cell surface proteins

• T cells which express a TCR that binds Antigen-MHC complexes, CD3 signal transduction, and CD28 binds B7 on APC.
• Helper T cells which have CD4 that binds HIV ,cytotoxic T cells as well as regulatory T cells, which have a combination of regulatory mechanisms.
• B cells, NK cells, Macrophages which each have distinct molecules for immune recognition and hematopoietic stem cells has a surface molecule named CD34.

Anergy

• State during which a cell can not become activated by exposure to its antigen.
• T and B cells become anergic when exposed to their antigen without costimulatory signal 2,another mechanism of self tolerance.

Passive vs Active Immunity

• Passive immunity is is where you receive Preformed antibodies with and it occurs rapidly but has short duration and for example IgA in breast milk.
• Active immunity means you are exposed to exogenous antigens slowly it last for a long time as well as Memory, for examples with natural infection and and vaccination.
• Combined passive and active immunizations can be given for hepatitis B or rabies exposure.

Types of Vaccine

• The live attenuated vaccine where you are microorganisms rendered non Pathogen, these vaccines induce cellular and humeral response and they have a strong and lifelong immunity they are used in viral based vaccines.
• Killed or inactivated is a pathological agent and is inactivated and it uses all use specific antigens that best stimulate the immune system.
• ,Subunit recombinant polysaccharide and Conjugate which have lower chance of adverse reactions, but they are more expensive.
• A toxoid is a Denatured bacterial toxin with an intact receptor binding website,they are used for bacteria antigen and they protect against bactetoxins where there are lower and lower boosters.
• mRNA A lipid nanoparticle that delivers mRNA, this process is pretty efficient.

Hypersensitivity

• Four types Anaphylactic,antibody mediated , immune complex cell mediated.

Type 1 Hypersensitivity

• Allergen crosses the antigens for degranulation after histamine release where the blood test is for allergen specific ige such as food and rug allergies.

Type 2 Hypersensitivity

• Antibodies bind to cell surface antigens for selling either inflammation of dysfunctions.
• In cellular distruction the cell is coated, with cell killing
• Type3 hypersensitivity
• An immune complex is triggered with a sub type IgG which attracts Neutrophils for inflammation can be associated with vasculinities.

Type 4 sensitivity

• Is a type 2 mechanism each of these are involving T cells as such direct cell cytotoxicity or inflammatory reaction for PPD on TB as well as transplant rejections.

Immunologic blood transfusion reactions

Is where different blood types are coming together due to the immune system and this is related to transfusions, which shows where red blood cells are coming apart and for allergies.

Auto Antibodies

• A diverse group is an antibody by Anti postsynaptic which Can cause acetylcholine receptor for myasthenia gravis, A

Immunodeficiencies

Are where the immune system is not working is designed for B cells and there is a long list and then there is T cell and different diseases for those and then finally there is B cell and T helper cells.

Transplant rejection

• Is different depending on whether it is pre assisting.
• For a week two months it is cellular as the immune system Is trying to act on the transplant.