3 - USMLE Endpoint - Step 1 - Immunology

Lymphoid Structures and Immune System Organs

• Primary Organs (Lymphocyte Maturation)
  • Bone Marrow: Immune cell production, B cell maturation.
  • Thymus: T cell maturation.
• Secondary Organs (Lymphocyte Activation)
  • Spleen, lymph nodes, tonsils, mucosal associated lymphoid tissue (MALT), cutaneous associated lymphoid tissue.
  • Allow immune cells to interact with antigens.

Lymph Node

• A secondary lymphoid organ with many afferents and one or more efferents.
• Encapsulated with trabeculae.
• Functions:
  • Macrophages: Nonspecific filtration.
  • Storage of B and T cells.
  • Immune response activation.
  • Site where plasma cells synthesize antibodies.

1. Cortex

• Follicles:
  • Site of B-cell localization and proliferation in the outer cortex.
  • Primary follicles: Dense and dormant.
  • Secondary follicles: Have pale central germinal centers and are active (proliferating B cells).
  • In agammaglobulinemia, germinal centers and primary lymphoid follicles do not form due to the absence of B cells.

2. Medulla

• Consists of:
  • Medullary cords: Closely packed lymphocytes and plasma cells.
  • Medullary sinuses: Communicate with efferent lymphatics and contain reticular cells and macrophages.

3. Paracortex

• Houses T cells.
• Region of cortex between follicles and medulla.
• Contains high endothelial venules through which T and B cells enter from the blood.
• Not well developed in patients with DiGeorge syndrome.
• Paracortex enlarges in extreme cellular immune responses (e.g., viral infection).

Mucosa-Associated Lymphoid Tissue (MALT)

• Unencapsulated lymphoid tissue lining the respiratory tract, digestive tract, and genitourinary tract.
  • Often divided into gut-associated lymphoid tissue (GALT), bronchus-associated lymphoid tissue (BALT), and nasal-associated lymphoid tissue (NALT).
  • GALT contains highly organized lymphoid tissue known as Peyer's patches.
    • Found in the lamina propria and submucosa of the ileum.
    • Separated from the intestinal lumen by microfold cells (M cells).
    • M cells constantly sample the intestinal lumen and transcytose antigens to underlying Peyer's patches.
    • APCs phagocytose the antigens and present them to resident T cells and B cells.

Lymph Drainage Associations

• Cervical:
  • Drains the head and neck.
  • Associated with upper respiratory tract infection, infectious mononucleosis, and Kawasaki disease.
• Mediastinal:
  • Drains the trachea and esophagus.
  • Associated with primary lung cancer.
• Hilar:
  • Drains the lungs.
  • Associated with granulomatous disease.
• Axillary:
  • Drains the upper limb, breast, and skin above the umbilicus.
  • Associated with mastitis and metastasis (especially breast cancer).
• Celiac:
  • Drains the liver, stomach, spleen, pancreas, and upper duodenum.
  • Associated with mesenteric lymphadenitis.
• Superior Mesenteric:
  • Drains the lower duodenum, jejunum, ileum, and colon to the splenic flexure.
  • Associated with typhoid fever, ulcerative colitis, and celiac disease.
• Inferior Mesenteric:
  • Drains the colon from the splenic flexure to the upper rectum.
  • Associated with metastasis.
• Para-aortic:
  • Drains the testes, ovaries, kidneys, and uterus.
  • Associated with sexually transmitted infections.
• Internal Iliac:
  • Drains the lower rectum to anal canal (above the pectinate line), bladder, vagina (middle third), cervix, and prostate.
• Superficial Inguinal:
  • Drains the anal canal (below the pectinate line), skin below the umbilicus (except popliteal area), scrotum, and vulva.
• Popliteal:
  • Drains the dorsolateral foot and posterior calf.
  • Associated with foot/leg cellulitis.
• Right Lymphatic Duct:
  • Drains the right side of the body above the diaphragm into the junction of the right subclavian and internal jugular vein.
• Thoracic Duct:
  • Drains everything else into the junction of the left subclavian and internal jugular veins.
  • Rupture can cause chylothorax.

Spleen

• Located in the left upper quadrant (LUQ) of the abdomen, anterior to the left kidney, protected by the 9th-11th ribs.
• Contains white pulp and red pulp, surrounded by a fibrous capsule.

1. Red Pulp

• Contains large numbers of red blood cells.
  • Sinusoids are long, vascular channels with fenestrated basement membranes.

2. Macrophages and APCs

• Phagocytose antigens in the red pulp and bring them to the marginal zone surrounding the white pulp.
• Present antigens to lymphocytes in the white pulp.

3. White Pulp

• Contains large numbers of white blood cells.
  • Central artery surrounded by a band of T cells called the periarterial lymphatic sheath (PALS).
  • Also contains organized follicles of B cells.

4. Platelet Sequestration

• The spleen sequesters roughly one-third of the body’s platelets.

Location of Immune Cells in Spleen

• T cells: PALS within the white pulp.
• B cells: Follicles within the white pulp.
• Macrophages: Marginal zone, where APCs capture blood-borne antigens.
  • Macrophages remove encapsulated organisms.

Splenic Dysfunction

• ↓ IgM → ↓ complement activation → ↓ C3b opsonization → ↑ susceptibility to encapsulated organisms.
• Vaccinate patients undergoing splenectomy against encapsulated organisms (pneumococcal, Hib, meningococcal).

Postsplenectomy

• Howell-Jolly bodies (nuclear remnants).
• Target cells.
• Thrombocytosis (loss of sequestration and removal).
• Lymphocytosis (loss of sequestration).

Thymus

• Derived from the third branchial pouch; enlarges during childhood and then atrophies in puberty.
• Located in the anterosuperior mediastinum.
• Site of T-cell differentiation and maturation.
• Encapsulated.

Structure

• Cortex:
  • Dense with immature T cells.
• Medulla:
  • Pale with mature T cells and Hassall corpuscles containing epithelial reticular cells.

Pathology

• Hypoplastic in DiGeorge syndrome and severe combined immunodeficiency (SCID).
• Thymoma:
  • Benign neoplasm of the thymus.
  • Associated with myasthenia gravis and superior vena cava syndrome.
• Normal neonatal thymus is sail-shaped on CXR, involutes with age.

Innate vs. Adaptive Immunity

• Major adaptive immune mechanisms that prevent reinfection with the influenza virus include anti-hemagglutinin antibodies.
• Antibodies to neuraminidase provide some protective effect (decrease the extent of viral invasion and shedding), but are not the main source of protection against reinfection.

Major Histocompatibility Complex (MHC) I and II

• MHC encoded by HLA genes.
• Present antigen fragments to T cells and bind T-cell receptors (TCRs).

MHC Class I Pathway

• Presents self-antigen, tumor antigen, or antigen synthesized by the cell due to viral infection.
• Referred to as the endogenous pathway.
• Proteins in the cytoplasm are degraded by a proteasome and then transported into the rough endoplasmic reticulum where they are loaded onto MHC Class I molecules by TAP and subsequently routed to the cell surface via the Golgi apparatus.
• Proteins are never processed within acidified lysosomes.

MHC Class II Pathway

• Material in the environment (bacterial organisms, viral particles, or freely circulating antigenic material) is taken up by antigen-presenting cells and degraded by acidification after endosome-lysosome fusion or phagosome-lysosome fusion.
• MHC Class II molecules are synthesized in the rough endoplasmic reticulum and routed to the endosomes by the Golgi apparatus.
• Each MHC class II molecule has an invariant chain bound to its antigen-binding site.
  • The invariant chain guides the MHC Class II molecule during sorting in the Golgi and occupies the binding site until the molecule enters an acidified endosome where it can bind foreign protein.
• Fusion of the vesicles containing MHC Class II with the acidified phagolysosomes containing foreign antigen leads to degradation of the invariant chain and loading of antigen onto the MHC Class II molecule.
• The MHC Class II molecule-protein antigen complexes are then displayed on the surface of antigen-presenting cells where they are available to bind the T-cell receptors (TCR) on T-lymphocytes and initiate a T-cell response to the antigen they display.
• Without lysosomal acidification, antigen processing in association with MHC class II antigens would not occur, and MHC Class II would be unable to bind antigen and therefore, unable to bind the TCR.
• HLA subtypes associated with diseases

Natural Killer (NK) Cells

• Part of the innate immune system and function similarly to CD8+ CTLs with some differences:
  • Express neither CD8 nor CD4 on their cell surfaces.
    • Identified by specific markers (CD16, CD56).
  • Do not require the thymus for maturation and are present in athymic patients.
  • Have no antigen-specific activities, do not require exposure to antigen for activation, and do not possess antigen memory ability.
• Activity enhanced by:
  • IL-2, IL-12, IFN-α, and IFN-β.
• Secretes:
  • IFN-γ  activates macrophages.
• Induced to kill when:
  • Exposed to a nonspecific activation signal on target cell.
  • An absence of MHC I on target cell surface.
• Kill by:
  • Perforin and granzymes to induce apoptosis of virally infected cells and tumor cells (do not directly lyse cells).
  • Antibody-dependent cell-mediated cytotoxicity (CD16 binds Fc region of bound Ig, activating the NK cell).

Major Functions of B and T Cells

B Cells

• Humoral immunity.
• Recognize 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 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 × CD4 = 8; MHC I × CD8 = 8.
• Differentiation of T cells

Positive Selection

• Thymic cortex.
• The process by which only T cells expressing a TCR that is able to bind self MHC are allowed to survive.
• Those cells expressing a TCR that is not specific for self MHC are signaled for elimination by apoptosis.
• Involves interaction of T cells with thymic cortical epithelial cells expressing self MHC.

Negative Selection

• Thymic medulla.
• T cells expressing TCRs with high affinity for self-antigens undergo apoptosis or become regulatory T cells.
• Involves interaction of the developing T cells with thymic medullary epithelial and dendritic cells.
• This process serves to eliminate T cells that may be overly autoreactive against self-antigens and therefore may play a role in autoimmunity if not destroyed.
• Tissue-restricted self-antigens are expressed in the thymus due to the action of autoimmune regulator (AIRE); deficiency leads to autoimmune polyendocrine syndrome-1.

Antigen Receptors of B and T Lymphocytes

• With flow cytometry, a cell is found to have both CD4 & CD8 surface antigens  Immature cortical T lymphocytes.
  • Immature T-lymphocytes express both the CD4 and CD8 cell surface antigens in addition to a complete TCR. These lymphocytes exist in the thymic cortex where they undergo positive selection and in the thymic medulla where they undergo negative selection.

Apoptosis in Lymphocytes

• The Fas receptor is expressed on T-lymphocytes and plays an important role in the pathogenesis of numerous diseases, including cancer and autoimmune disorders.
• Once activated, T lymphocytes begin to express FasL, which can bind to Fas on the same cell or adjacent lymphocytes.
• During initial clonal expansion, activated T lymphocytes are resistant to Fas-induced apoptosis.
• However, they become more sensitive with progressive stimulation.
• In the constant presence of stimulating self-antigens, activated T lymphocytes eventually undergo apoptosis in a process known as activation-induced cell death.
• Mutations involving Fas or FasL impair this process resulting in excessive accumulation of autoreactive T-cells and the development of autoimmune diseases such as systemic lupus erythematosus.

Helper T Cells

• Factors in T-Helper cell differentiation
  • TH1:
    • Secrete IFN-γ and IL-2.
    • Activation of macrophages and CD8+ T-cells.
    • Mediation of delayed-type hypersensitivity.
    • Differentiation induced by IFN-γ and IL-12.
    • Inhibited by IL-4 and IL-10 (from Th2 cell).
  • TH2:
    • Secrete IL-4, IL-5, IL-6, IL-10, IL-13.
    • Initiation of antibody response.
    • Regulation of immunoglobulin class switching.
    • Recruits eosinophils for parasite defense and promotes IgE production by B cells.
    • Differentiation induced by IL-2 and IL-4.
    • Inhibited by IFN-γ (from Th1 cell).
• Macrophage-lymphocyte interaction-dendritic cells, macrophages, and other APCs release IL-12, which stimulates T cells to differentiate into Th1 cells. Th1 cells release IFN-γ to stimulate macrophages.
• Helper T cells have CD4, which binds to MHC II on APCs.

Granuloma Formation

• Manifestation of cell-mediated immunity.
• Driven by products of TH1 type CD4+ helper T cells:
  • IL-2  stimulates TH1 type cell proliferation (autocrine).
  • Interferon-γ (IFN-γ)  macrophage activation.
• Langhans giant cells are characteristic of granulomatous conditions.
  • They have multiple nuclei peripherally organized in the shape of a horseshoe.
  • The macrophages that form these giant cells are activated by TH1 lymphocytes.
• CD4+ T helper cells are the predominant type of lymphocyte found in sarcoid granulomas.
  • Intraalveolar and interstitial accumulation of CD4+ T cells in sarcoidosis often results in high CD4+/CD8+ T-cell ratios in bronchoalveolar lavage fluid.

Cytotoxic T Cells

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

Regulatory T Cells

• Functions (inhibitory to the immune system):
  • Inhibit B cells from producing antibodies.
  • Inhibit CD4 and CD8 T-cells.
  • Activated regulatory T cells (Tregs) produce anti-inflammatory cytokines (e.g., IL-10, TGF-β).
  • Dysfunction of regulatory T cells has been strongly implicated in many autoimmune disorders.
• Identified by:
  • Expression of CD3, CD4, CD25, and FOXP3.
• 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.

T-Cell Activation

• 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

• T cells require two signals for activation.
• Dendritic cell (specialized APC) samples antigen, processes antigen, and migrates to the draining lymph node.
• Th cell activation:
  1. The first signal involves binding of the TCR (CD4) to MHC class II on an APC.
  2. The second signal (or co-stimulatory signal) commonly comes from the engagement of CD28 on the T cell with B7 (either CD80 or CD86) on the APC.
  3. Alternatively, the co-stimulatory signal may come from cytokines such as IL-2.
• Tc cell activation:
  1. The first signal involves binding of the TCR (CD8) to MHC class I on infected/damaged cells.
  2. The co-stimulatory signal is the same as in Th cell activation.
• Macrophage lymphocyte interaction
  1. Th1 cells secrete IFN-γ, which enhances the ability of monocytes and macrophages to kill microbes they ingest.
  2. This function is also enhanced by interaction of T cell CD40L with CD40 on macrophages.

B Cells Activation and Functions

• B-cell function:
  1. The main function of B cells is to produce antibodies to support the adaptive immune response.
  2. B cells are defined by the surface expression of CD19, CD20, CD21, as well as IgM and IgD.
  3. After encountering antigen and becoming activated, they transform into plasma cells, which produce large quantities of Ig against that antigen.
     • B cells are mainly activated by cytokines produced by Th2 cells, such as IL-4, IL-5, and TGF-β.
  4. Once activated, some B cells become memory B cells, which lie dormant until they encounter their cognate antigen again, at which point they can rapidly begin producing antibodies in response.
     • Memory B cells decrease in number with age. This is why vaccine efficacy is decreased in the elderly.
  5. B cells that produce Igs against self-antigens are signaled to undergo apoptosis in the bone marrow in a negative selection process similar to that seen in thymic T cells.

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 CD40 ligand (CD40L) on Th cell.
4. Th cell secretes cytokines that determine Ig class switching of B cell.

Dendritic Cells

• Covered by long membranous extensions resembling the dendrites of nerve cells.
• All display class I and II MHC and a B7 protein (either CD80 or CD86).
• All also have CD40 which can interact with T-cells to further activate the antigen-presenting cell.
• Purpose: capture Ag at one site and present Ag at another location. This is accomplished by migration to the LN for presentation to the T cells.
• Different types:
  • Langerhans cells, found in the epidermal layer of the skin (cutaneous-associated lymphoid tissue)
  • Interstitial dendritic cells, in all organs except brain

Antibody Structure and Function

• Fab region:
  1. Containing the variable/hypervariable regions.
  2. Consisting of light (L) and heavy (H) chains recognizes antigens.
     • 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
  • 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) genes.
   • The main mechanism by which a static genome can generate highly variable Fab regions to bind to a nearly infinite variety of antigens.
   • Variable (V), joining (J), and diverse (D) segments in the DNA undergo genetic rearrangement during B-cell development.
   • The recombinase-activating genes 1 and 2 (RAG1, RAG2) facilitate this process. Mutations in either of these genes results in severe combined immunodeficiency as this process is occurring in both B cell (Igs) and T cells (TCRs).
   • V(J)D recombination is also responsible for generating diverse TCRs.
2. Random addition of nucleotides to DNA during recombination by terminal deoxynucleotidyl transferase (TdT).
   • Adds bases into the DNA strand each time V, D, and J segments are spliced, in a random fashion.
3. Random combination of heavy chains with light chains.

Generation of Antibody Specificity (Antigen Dependent)

1. Somatic hypermutation and affinity maturation (variable region)
   • Somatic hypermutation:
     1. Within the germinal center of the lymph node, affinity maturation is accomplished by the process of somatic hypermutation where the DNA coding for the immunoglobulin variable region is mutated randomly at a very high rate.
     2. This process results in new immunoglobulins with similar, better, or worse affinity for the antigen; only B cells expressing antibody with enhanced affinity for antigen will be selected for.
     3. This occurs after a B cell recognizes an antigen and becomes activated.
     4. The resulting antibody will usually still recognize the target antigen, but, depending on the mutations, its affinity may be either increased or decreased.
     5. B cells that produce antibodies with higher affinity will be preferentially activated as more antigen is encountered, causing them to proliferate.
2. Isotype switching (constant region)
3. Antibody functions:
   • Bind to antigen.
   • Neutralize the pathogen.
   • Opsonize the pathogen.
   • Activate the complement (Fc region of IgM and IgG fixes complement  MAC.)

Immunoglobulin Isotypes

• 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.
• Isotype class switching: (from IgM to other types of immunoglobulins)
  1. The primary immune response to a new antigen initially results in plasma cells that only produce IgM.
  2. Isotype switching later occurs in the germinal centers of lymph nodes and requires interaction of the CD40 receptor on B-cells with the CD40 ligand (CD154) expressed by activated T-cells.
  3. IgG is the main serum immunoglobulin of the secondary response.

IgG

• Main antibody in 2° (delayed) response to an antigen.
• Most abundant isotype in serum.
• Functions:
  1. Fixes complement.
  2. Opsonizes bacteria, neutralizes bacterial toxins and viruses.
  3. Crosses the placenta (provides infants with passive immunity).
• Half-life is about 21 days.

IgA

• Prevents attachment of bacteria and viruses to mucous membranes.
• Does not fix complement.
• Monomer (in circulation) or dimer (with J chain when secreted).
  1. Secretory IgA is formed from the association of ten distinct protein molecules.
  2. These ten proteins include four immunoglobulin light chains and four immunoglobulin heavy chains to form the two IgA molecules, one protein known as the J chain, and a final protein known as the secretory component.
  3. While most of the components of the molecule are produced by plasma cells, the secretory piece is synthesized by epithelial cells.
  4. This component facilitates the movement of secretory IgA through the mucosal membranes and prevents its degradation in secretions.
• Crosses epithelial cells by transcytosis.
• Produced in the GI tract (e.g., by Peyer patches) and protects against gut infections (e.g., Giardia).
  1. Selective IgA deficiency  recurrent giardiasis.
• Most produced antibody overall, but has lower serum concentrations.
• Released into secretions (tears, saliva, and mucus) and breast milk.
  1. Particularly important as a component of the colostrum, or the first breast milk fed to an infant after birth, where it functions to provide the infant with passive mucosal immunity.
• The live attenuated oral (Sabin) poliovirus vaccine produces a stronger mucosal secretory IgA immune response than does the inactivated poliovirus (Salk) vaccine. This increase in mucosal IgA offers immune protection at the site of viral entry by inhibiting attachment to intestinal epithelial cells.
• Certain bacteria (e.g., N gonorrhoeae, N meningitidis, Streptococcus pneumoniae, Haemophilus influenzae) produce IgA proteases that cleave IgA at its hinge region (yielding Fab and compromised Fc fragments), thus decreasing its effectiveness. This facilitates bacterial adherence to mucosa (possibly due to easier bacterial access to the mucosal surface or immune disguise by binding to released Fab fragments among others).

IgM

• Produced in the 1° (immediate) response to an antigen.
• Fixes complement but does not 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 the humoral response evolves.

IgD

• Unclear function. Found on the surface of many B cells and 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.
• Lowest concentration in serum.
• Contributes to immunity to worms by activating eosinophils.
  • Eosinophils play a role in host defense during parasitic infection. When stimulated by antibodies bound to a parasitic organism, they destroy the parasite via antibody-dependent cell-mediated cytotoxicity with enzymes from their cytoplasmic granules.
• Omalizumab (anti-IgE) is used in moderate-to-severe asthma.
  • Many asthmatics frequently have allergies as a trigger due to a high IgE response in the body.
  • Omalizumab decreases the allergic response.
  • Studies have shown that patients receiving omalizumab have fewer exacerbations of asthma and are able to discontinue the use of oral glucocorticoids and decrease the dose of inhaled steroids.

Antigen Type and Memory

Thymus-Independent Antigens

• Antigens lacking a peptide component (e.g., lipopolysaccharides from gram-negative bacteria); cannot be presented by MHC to T cells.
• Weakly immunogenic; vaccines often require boosters and adjuvants (e.g., pneumococcal polysaccharide vaccine).
  1. Streptococcus pneumonia, Neisseria meningitidis, and Haemophilus influenza are encapsulated bacteria whose polysaccharide capsule components can be covalently bound to protein carriers and used as vaccine antigens.
  2. The protein carriers convert the polysaccharides from T-cell independent to T-cell dependent antigens.
  3. Approved carrier proteins include:
     • Mutant nontoxic diphtheria toxin.
     • Neisseria meningitidis outer membrane protein complex.
     • Tetanus toxoid.

Thymus-Dependent Antigens

• Antigens containing a protein component (e.g., diphtheria vaccine).
• Class switching and immunologic memory occur as a result of direct contact of B cells with Th cells.

Acute-Phase Reactants

• Factors whose serum concentrations change significantly in response to inflammation.
• Produced by the liver in both acute and chronic inflammatory states.
• Induced by IL-6.

Positive (Upregulated)

• C-reactive protein:
  • Opsonin  facilitates phagocytosis.
  • Fixes complement.
  • Measured clinically as a nonspecific sign of ongoing inflammation.
• Ferritin:
  • Binds and sequesters iron to inhibit microbial iron scavenging.
• Fibrinogen:
  • Coagulation factor; promotes endothelial repair.
  • Correlates with ESR.
• Hepcidin:
  • ↓ Iron absorption (by degrading ferroportin) and ↓ iron release (from macrophages)  anemia of chronic disease.
• Serum amyloid A:
  • Prolonged elevation can lead to amyloidosis.

Negative (Downregulated)

• Albumin:
  • Reduction conserves amino acids for positive reactants.
• Transferrin:
  • Internalized by macrophages to sequester iron.

Complement

• System of hepatically synthesized plasma proteins that play a role in innate immunity and inflammation.
• Membrane attack complex (MAC) defends against gram-negative bacteria.

Activation

• Classic pathway  by IgG or IgM mediated. (GM makes classic cars.)
• Alternative pathway  by microbe surface molecules.
• Lectin pathway  by mannose or other sugars on microbe surface.

Functions

• C3b—opsonization (C3b binds bacteria).
• 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

• Prevent complement activation on self-cells (e.g., RBCs).
• Decay-accelerating factor (DAF, aka CD55).
• C1 esterase inhibitor.

Complement Disorders

Complement Protein Deficiencies

• Early complement deficiency (C1-C4):
  • Increased risk of severe, recurrent pyogenic sinus and respiratory tract infections.
  • Increased risk of SLE.
  • ↑ Susceptibility to type III hypersensitivity reactions.
• Terminal complement deficiencies (C5–C9) (membrane attack complex):
  • ↑ Susceptibility to recurrent Neisseria bacteremia.
    • N. meningitides presents with high fever, chills, altered mentation, petechial skin rash from Neisseria-induced small-vessel vasculitis (especially affecting palms and soles), and ultimately septic shock.
    • The treatment is intravenous ceftriaxone for at least 2 weeks.

Complement Regulatory Protein Deficiencies

• C1 esterase inhibitor deficiency:
  • Causes hereditary angioedema due to unregulated activation of kallikrein  ↑ bradykinin.
  • Characterized by ↓ C4 levels.
  • ACE inhibitors are contraindicated.
    • C1 esterase inhibitor is inhibited directly by bradykinin, which explains the rare but life-threatening angioedema that may result as a side effect of angiotensin-converting enzyme (ACE) inhibitors (ACE is responsible for the degradation of bradykinin).
• Paroxysmal nocturnal hemoglobinuria (CD55 deficiency):
  • A defect in the PIGA gene preventing the formation of anchors for complement inhibitors, such as decay-accelerating factor (DAF/CD55) and membrane inhibitor of reactive lysis (MIRL/CD59).
  • Causes complement-mediated lysis of RBCs.

Important Cytokines

• Hematopoiesis

Cytokines Secreted by Macrophages

• IL-1:
  • Causes fever, acute inflammation.
  • Activates endothelium to express adhesion molecules.
  • Induces chemokine secretion to recruit WBCs.
• IL-6:
  • Causes fever.
  • Stimulates production of acute-phase proteins.
• IL-8:
  • Major chemotactic factor for neutrophils.
  • Recruits neutrophils to clear infections.
  • Also induces phagocytosis in neutrophils once they have arrived.
• IL-12:
  • Induces differentiation of T cells into Th1 cells.
  • Activates NK cells.
• TNF-α:
  • Produced by macrophages in response to bacterial endotoxin and causes symptoms of septic shock (e.g., fever, hypotension, and tachycardia) when released in large amounts.
  • Pro-inflammatory:
    • Activates endothelium, causes WBC recruitment, vascular leak.
    • IL-1, IL-6, and TNF-α can mediate sepsis.
  • Causes cachexia in malignancy.
  • Maintains granulomas in TB.
  • TNF-α is directly inhibited by the monoclonal antibodies infliximab, adalimumab, and golimumab as well as the fusion protein etanercept.

Cytokines Secreted by All T Cells

• IL-2:
  • Functions:
    • Stimulates growth of helper, cytotoxic, and regulatory T cells, and NK cells.
  • Secreted by:
    • T helper cells.
    • Antigen binding to the T cell receptor stimulates the secretion of IL-2 and the expression of IL-2 receptors (IL-2R).
  • Drugs:
    • Recombinant IL-2 (aldesleukin) is used to treat metastatic renal cell carcinoma and metastatic melanoma.
    • Basiliximab, which blocks the action of IL-2 by binding the IL-2 receptor on cells, is used to prevent transplant rejection.
• IL-3:
  • Supports growth and differentiation of bone marrow stem cells.
  • Functions like GM-CSF.

Cytokines From Th1 Cells

• Interferon-γ:
  • Secreted by:
    • NK cells and T cells in response to antigen or IL-12 from macrophages.
  • Functions:
    • Stimulates macrophages to kill phagocytosed pathogens.
    • Inhibits differentiation of Th2 cells.
    • Also activates NK cells to kill virus-infected cells.
    • Increases MHC expression and antigen presentation by all cells.
• Autosomal recessive deficiencies of the IFN-gamma receptor (or other elements of this pathway) result in disseminated mycobacterial disease in infancy or early childhood, including disseminated infection by the BCG vaccine strain if administered. Once identified, these patients require lifelong treatment with continuous antimycobacterial antibiotics.
• Pulmonary tuberculosis infection is controlled through the action of CD4+, TH1 lymphocytes and macrophages. These cells work together to contain M. tuberculosis