Inmuno HY Mehlman - Info and Questions

Cell-mediated immunity means

"T cell-mediated" immunity that does not involve antibodies in order to kill the organism § Cytotoxic CD8+ T cells kill nucleated cells that present intracellular antigen on MHC I molecules, where the CD8+ T cell releases granzymes, granulysins, and perforins, inducing apoptosis of the target cell. This does not involve antibody and is therefore cell-mediated, not humoral, immunity. § Th1 CD4+ cells activate macrophages via the IFN-γ-IL-12 loop to kill phagocytosed organisms. No antibody is made in relation to this process. § CD8+, Th1 CD4+ T cells, and macrophages are therefore part of cell-mediated immunity. § Dendritic cells are another type of APC that are part of both humoral and cellmediated immunity, depending on if the MHC II-TCR interaction results in a Th1 (cell-mediated) or Th2 (humoral) response. In short: § Humoral immunity = B cells and Th2 CD4+ T cells § Cell-mediated immunity = CD8+, Th1 CD4+ T cells, and macrophages. § It is inaccurate to say the difference between cell-mediated and humoral immunity is strictly CD4+ vs CD8+. This is because CD4+ Th1 cells contribute to cell-mediated immunity; CD4+ Th2 contribute to humoral immunity.

Paroxysmal nocturnal hemoglobinuria is caused by

"increased complement-mediated lysis" of RBCs. It is caused by deficiency of GPI anchor, which "anchors" CD55 (decay-acceleratory factor) and protectin (CD59) to the RBC cell surface. CD55/59 protect the RBC from complement-mediated lysi

Immune thrombocytopenic purpura

(aka idiopathic thrombocytopenic purpura) Anti-GpIIb/IIIa on platelets (platelet aggregation)

TGF-b

- Anti-inflammatory cytokine, similar to IL-10 (i.e., when you think of TGF-b and IL-10, think decrease inflammation). - TGF-b and IL-6 stimulate Th0 -> Th17. - TGF-b stimulates Th0 à Treg.

IL 4

- Both IL -4 and IL -10 stimulate Th0 -> Th2, and inhibit Th0 -> Th1. - Therefore IL -4 functions to ultimately increase CD4+ activation of B cells. - This means this cytokine is important for supporting humoral immunity.

IL 12

- Both IL-12 and IFN-γ stimulate Th0 -> Th1, and inhibit Th0 -> Th2. - Stimulates Th1 cells to make IFN-γ. - IL-12 receptor deficiency is associated with increased TB infections (i.e., decreased IL-12 response -> decreased IFN-γ -> decreased macrophage activity -> increased risk for TB infections); treat with IFN-γ. - Stimulates NK cells.

IL-1

- Causes fever. - If the Q tells you a guy with sepsis has low BP and fever, they want TNF-a and IL-1 as the two cytokines responsible; if you're forced to choose only one cytokine for septic shock, choose TNF-a, but if they ask specifically about the fever, choose IL-1. - Also known as osteoclast-activating factor; can contribute to post-menopausal osteoporosis and lytic lesions of bone in the setting of metastases and multiple myeloma; USMLE Q might show you a pic of an osteoporotic vertebra, and then the answer is just "increased IL-1 activity." IL-6 also plays a role in osteoporosis, but NBME for Step 1 has IL-1 as many answers - If the Q tells you an NSAID is used to decrease fever, choose prostaglandin, not IL -1, as the molecule responsible for fever

IL 10

- HY as an anti -inflammatory cytokine that plays a role in suppressing various immune responses. If the USMLE asks which cytokine can decrease an immune response, choose IL -10 (or TGF - b). - Both IL -10 and IL -4 stimulate Th0 à->Th2, and inhibit Th0 -> Th1. - Therefore IL -10 functions to ultimately increase CD4+ activation of B cells. - This means this cytokine is important for supporting humoral immunity

IFN-γ

- HY cytokine produced by Th1 CD4+ T cells that stimulates macrophages. - Macrophages stimulated by IFN-γ produce IL-12. - Both IFN-γ and IL-12 stimulate Th0 -> Th1, and inhibit Th0 -> Th2. - Used in the Tx of NADPH oxidase deficiency (chronic granulomatous disease).

"What do I need to know about B cells?"

- Main cell of humoral immunity; differentiates into antibody-secreting plasma cell. - Undergoes somatic hypermutation and affinity maturation, enabling increased antibody specificity for antigen. - Areas within lymph nodes and the spleen where B cells proliferate and differentiate are known as germinal centers. - Type of antigen-presenting cell (APC), meaning it can phagocytose extracellular pathogen and present it to CD4+ T cells on MHC II

IL 8

- Neutrophilic chemotactic molecule - IL-8, C5a, LTB-4, platelet-activating factor, kallikrein, and bacterial products all stimulate neutrophilic chemotaxis

IL 3

- Stimulates myeloid lineage (i.e., mostly neutrophils); think of IL -3 as similar to GM - CSF.

IL 11

- Stimulates platelets. - Oprelvekin is a recombinant IL -11 that can be used to stimulate thrombopoiesis post - chemotherapy.

"What do I need to know about T cells?

- Two main types to know for USMLE: CD8+ and CD4+. - Cytotoxic CD8+ T cells kill intracellular organisms (i.e., mostly viruses, some bacteria). Its T cell receptor (TCR) binds to MHC I on all nucleated cells. Once activated, it will release cytotoxic granzymes, granulysins, and perforins, causing apoptosis of the target (infected) cell. - CD4+ T cells have many types. Th0 is an upstream CD4+ T cell subtype. This can differentiate into, most importantly, Th1 and Th2. Th1 primarily activates macrophages. Th2 primarily stimulates B cells, enabling antibody production

"What do I need to know about T cell activation?"

- When a cell loaded with antigen on MHC I or II comes into contact with a CD8+ T cell (aka cytotoxic T cell) or CD4+ T cell (aka Helper T cell), respectively, the primary signal is merely the binding of MHC to both TCR and the CD molecule. In other words: § MHC I binds to TCR + CD8. § MHC II binds to TCR + CD4. - A secondary signal then ensues: B7-1 (CD80) or B7-2 (CD86) on the nucleated cell / APC binds to CD28 on the naive T cell. The T cell is now activated. In other words, the second step is: § B7-1/-2 (CD80/86) binds to CD28. § This second step is the same for both CD4+ and CD8+ T cells

"What do I need to know about natural killer (NK) cells?

-Part of innate immunity; stimulated by IL-12. - NK cells, B cells, and T cells are the three types of lymphocytes (all derived from lymphoid progenitors). - Kill viral-infected and tumor cells based on variation in cell surface protein expression (e.g., by identifying downregulation of cellular MHC I expression). - CD16 on NK cells enable a process called antibody-dependent cell-mediated cytotoxicity: § Antibodies produced by plasma B cells bind to antigen at their Fab regions, leaving Fc regions of the antibody facing outward. § CD16 on NK cells binds Fc regions of antibody. § Crosslinking of CD16 molecules occurs, causing the NK cell to release of granzymes, granulysins, and perforins, which induces apoptosis in target cell

CD80/86

Also known as B7-1/7-2; found on nucleated cells/APCs; bind to CD28 on T cells as secondary signal following primary MHC interaction

Addison disease

Anti-21-hydroxylase

Thrombotic thrombocytopenic purpura

Anti-ADAMTS13 (a matrix metalloproteinase that cleaves vWF multimers)

Small cell cerebellar dysfunction

Anti-Hu/-Yo; ataxia in someone with small cell lung cancer and negative CNS imaging

Polymyositis / Dermatomyositis

Anti-Jo1; can be a paraneoplastic of ovarian cancer

Sjogren syndrome

Anti-SS-A (anti-Ro); anti-SS-B (anti-La)

Graves disease

Anti-TSH receptor (this antibody is called thyroid stimulating immunoglobulin, or TSI, and activates the TSH receptor)

Neuromyelitis optica (Devic syndrome)

Anti-aquaporin 4 (asked on 2CK Neuro form)

Antiphospholipid syndrome

Anti-b2-microglobulin; anti-cardiolipin; lupus anticoagulant (the latter is the name for either of the former two if the patient happens to have SLE); Abs associated with recurrent miscarriage; can cause false-positive syphilis screening (e.g., SLE patient who gets positive syphilis VDRL test)

Limited-type systemic sclerosis / scleroderma

Anti-centromere

Goodpasture syndrome

Anti-collagen IV (anti-GBM; glomerular basement membrane); causes linear immunofluorescence on renal biopsy; don't confuse with Alport syndrome, which is mutations in type IV collagen (not Ab)

Pemphigus vulgaris

Anti-desmosome (anti-desmoglein 1 and 3); desmosomes connect adjacent cells in epidermis; cause a net-like immunofluorescence on skin biopsy

Systemic lupus erythematosus (SLE)

Anti-double-stranded DNA (dsDNA); anti-Smith (ribonucleoprotein); anti-hematologic cell line Abs; should be noted that dsDNA goes up in acute flares + best reflects renal prognosis; anti-Smith is more specific than anti-dsDNA; thrombocytopenia is an exceedingly HY finding in SLE due to Abs; if all cell lines are down in SLE, aplastic anemia (decreased bone marrow production) is wrong answer; choose "increased peripheral destruction" as answer

Celiac disease

Anti-endomysial (aka anti-gliadin); anti-tissue transglutaminase IgA; antibody screening will yield false-negatives if patient also has IgA deficiency

Type I diabetes mellitus

Anti-glutamic acid decarboxylase(anti-GAD); anti zinc transporter 8

Bullous pemphigoid

Anti-hemidesmosome (bullous pemphigoid antigen); hemidesmosomes connect the dermis to epidermis; cause a linear immunofluorescence on skin biopsy

Drug-induced lupus (DIL)

Anti-histone; caused by various drugs (Mom is HIPP) -> Minocycline, Hydralazine, INH, Procainamide,

Primary biliary cirrhosis

Anti-mitochondrial

Rheumatic heart disease

Anti-myosin; anti-valve-derived proteins; should be noted that these Abs are formed against S. pyogenes M protein and almost always cross-react with the mitral valve (molecular mimicry)

Pernicious anemia

Anti-parietal cell; anti-intrinsic factor

Primary membranous glomerulonephritis

Anti-phospholipase A2 receptor

Heparin-induced thrombocytopenia (HIT)

Anti-platelet factor 4-heparin complex (anti-PF4-heparin)

Lambert-Eaton

Anti-presynaptic voltage-gated calcium channel; sometimes a paraneoplastic of small cell lung cancer

Hashimoto thyroiditis

Anti-thyroperoxidase (anti-microsomal); anti thyroglobulin

Diffuse-type systemic sclerosis / scleroderma

Anti-topoisomerase I (Scl-70)

CD10

Associated with ALL

CD16 + CD56

Both on NK cells; CD16 binds Fc region of IgG and causes antibody-dependent cell-mediated cytotoxicity -> lysis of target cell by NK cell; CD56 is just a specific NK cell marker

Common pathway

C3 goes down in post-streptococcal glomerulonephritis (PSGN) and SLE flares. C4 goes down in cryoglobulinemia (discussed later) C3a, C4a, and C5a are known as anaphylatoxins, which can trigger degranulation of mast cells, causing anaphylaxi C5a is a neutrophilic chemotactic molecule (as with IL-8, LTB-4, kallikrein, platelet-activating factor, and bacterial products). Terminal complement deficiency (C5-9) is associated with recurrent Neisseria infections (both gonococcal and meningococcal). C1 esterase inhibitor deficiency (not C1 esterase; C1 esterase inhibitor) is associated with hereditary angioedema.

CD18

CD18 is a subunit of LFA-1 integrin found on various WBCs; deficiency of CD18/LFA-1 integrin causes leukocyte adhesion deficiency

MHC primary interaction

CD34 Ubiquitous on hematopoietic stem cells (i.e., not specific marker for, but found on all)

Listeria and viruses are?

Choose cell-mediated immunity for viruses and Listeria. For chronic mucocutaneous candidiasis, choose "deficiency of cell-mediated immunity" Choose "deficiency of humoral immunity" for IgA deficiency and Bruton XLA

CD55/59

Deficient in paroxysmal nocturnal hemoglobinuria

What do I need to know about T cell differentiation?

For USMLE purposes, this applies to just CD4+ T cells. In other words, they want you to know mostly about how Th0 can become Th1 and Th2 cells. As mentioned earlier, a Th0 cell is an upstream type of CD4+ T cell that has not yet differentiated. CD8+ T cells are more simplistic and are merely activated to kill target cells, but CD4+ T cells undergo various routes of differentiation in addition to their activation. o Th0 can become Th1, Th2, Th17, and Treg (regulatory) cells. Th1 cells stimulate macrophages, which kill phagocytosed pathogens and (if necessary) organize into granulomas. Th2 cells stimulate B cells to become plasma cells, which make antibodies that kill extracellular pathogens. Th17 cells stimulate neutrophilic production and recruitment. Treg cells prevent autoimmunity (i.e., are a suppressive type of T cell).

CD40

Found on macrophages and B cells; activated by CD40L on Th1 and Th2 cells, respectively; CD40L CD40 interaction between Th2 and B cells is responsible for isotype class-switching + B cell differentiation into plasma cells

CD3

Generic T cell marker; associated with TCR; binds to target cell MHC in addition to CD4/CD8

TNF-a

Increases vascular permeability; causes low BP in septic shock; if the USMLE asks which cytokine is most responsible for patient's presentation of septic shock, TNF-a is the answer. - Also known as cachexia factor -> is the main cytokine responsible for weight loss in the setting of malignancy (HY).

Th1 cells also stimulate?

It should be noted that Th1 cells also co-stimulate macrophages via CD40L-CD40 interaction, however on USMLE, this CD40L-CD40 interaction is specifically HY with respect to Th2 activation of B cells

CD4

Marker for T helper cells (Th0, Th1, Th2, Th17, Treg); binds to MHC II on APCs

CD8

Marker for cytotoxic T cells; binds to MHC I on nucleated cells

CD1a

Marker in Langerhan cell histiocytosis

"What do I need to know about the various cytokines

Memorize macrophages as secreting, most importantly: TNF-a, IL-1, IL-6, IL-8, and IL-12. Memorize IL-2 as a T cell stimulator. Memorize TNF-a and IL-1 as the two associated with sepsis: TNF-a causes low BP; IL-1 causes fever. Memorize IL-8 as a neutrophilic chemotactic molecule. Interferons can broadly facilitate with viral infections by inhibiting viral replication

Penicillamine

Myasthenia gravis Anti-post-synaptic acetylcholine receptor; sometimes a paraneoplastic of thymoma

"What do I need to know about the complement cascade/pathways? I hear about complement a lot but I'm not really sure what it does. Can you explain that

No, you do not need to memorize / draw out the complement pathways for Step 1. Waste of time. You just need to have a broad sense of the role complement plays in the innate immune system + some factoids about the different complement molecules. Complement proteins are acute phase proteins produced by the liver. There are three pathways for complement activation; they all lead to target cell death via formation of the membrane attack complex (MAC), composed of C5b-C9 complement proteins, or via stimulating opsonization and phagocytosis

CD28

On T cells; bound by B7-1/7-2 (CD80/86) on nucleated cells/APCs as secondary signal following

CD14

On macrophages; associated with toll-like receptor 4; binding of LPS endotoxin to CD14 results in macrophage release of TNF-a + IL-1 -> septic shock caused by endotoxin (do not confuse with septic shock caused by S. aureus TSST superantigen bridging TCR and MHC II -> toxic shock syndrome)

So the quick summary of T cell activation

Primary signal = MHC binds to TCR/CD. Secondary signal = B7 protein binds to CD28

CD21

Receptor for EBV entrance into B cells

CD25

Regulatory T cell (Treg) marker

Rheumatoid arthritis

Rheumatoid factor (an IgM against the Fc region of IgG); anti-cyclic citrullinated peptide (CCP); anti-CCP is more specific than rheumatoid factor

CD5 + CD23

Seen in CLL (sounds low-yield and pedantic but I've seen these on a few NBME Step 1 Qs)

CD15 + CD30

Seen on Reed-Sternberg cells in Hodgkin disease

CD19 + CD20

Specific B cell markers; rituximab is a monoclonal Ab against CD20; Q might mention a virus invading cells that are CD19/20 (+) and the answer is EBV (invades B cells)

Stimulated macrophages

Stimulated macrophages may or may not go on to form granulomas, which are dense clusters of organized macrophages that appear if inflammation is chronic. Activated macrophages composing a granuloma are called histiocytes, or epithelioid macrophages. § In short: IL-12/IFN-γ -> increased Th1 lineage -> increased macrophage activation. § Macrophages that organize into granulomas are called histiocytes, or epithelioid macrophages - Th0 -> Th2 occurs via stimulation with IL-4 and IL-10. The Th2 cell has a ligand on its cell surface called CD40 ligand (CD40L). This binds to CD40 on the B cell, activating it and facilitating its differentiation into a plasma cell. The plasma cell (or plasma B cell) then makes copious antibodies that neutralize extracellular pathogen (humoral immunity). In short: IL-4/IL-10 -> increase Th2 = B cell activation -> increase plasma cells -> increase Abs.

IL - 2

Stimulates T cells; when you think of IL -2, the first thing that should come to mind is, "Ok, that's the one that broadly activates T cells." - Cyclosporin and tacrolimus are HY drugs that decrease transcription of IL -2 via inhibiting calcineurin. - Sirolimus decreases responsiveness to IL -2. - Aldesleukin is a recombinant IL -2 used in the Tx of RCC and metastatic melanoma (essentially, increased T cell response helps fight cancer, and IL -2 increased T cell response)

IL 6

Stimulates acute -phase protein release from the liver (i.e., CRP, hepcidin). - Can cause osteoporosis. - Tocilizumab is a monoclonal Ab against IL -6 receptor used in severe rheumatoid arthritis. - IL -6 and TGF - b stimulate Th0 -> Th17

"Can you explain T cell migration through the thymus? What do I need to know?"

T cells migrate into the thymic cortex first as CD4 and CD8 negative. They then differentiate, still in the thymic cortex, into T cells that are both CD4+ and CD8+ (i.e., each T cell has both CD4 and 8 on its surface). Positive selection occurs in the cortex, where only T cells capable of binding self-MHC antigen survive (i.e., they're capable of generating an immune response). As T cells migrate from the cortex into the medulla, they lose either a CD4 or CD8, so the thymic medulla has CD4+ and CD8+ T cells (i.e., they don't simultaneously express both antigens anymore). Negative selection occurs in the medulla, where T cells capable of binding self-MHC antigen undergo apoptosis. This is a check to prevent autoimmunity The CD8+ T cell then leaves the thymic medulla for the lymph node, where it becomes a cytotoxic T cell. It will bind to MHC I on all nucleated cells via its T cell receptor (TCR). The CD4+ T cell leaves the thymic medulla for the lymph node, where it becomes a Helper T cell (Th cell; [Th0 initially]), which then can become many different subtypes of CD4+ T cells, including Th1, Th2, Th17, and Treg (regulatory T cells). The TCRs on these cells bind to MHC II on antigen-presenting cells (APC)

Th0

Th0 -> Th1 occurs via stimulation with IL-12 and IFN-l. IL-12 is secreted by macrophages. IFN-γ is secreted by Th1 cells. Once a Th0 cell becomes a Th1 cell, it activates macrophages via IFN-γ. Macrophages then secrete even more IL-12, which continues to stimulate more Th0 -> Th1 cells. This IL-12-IFN-γ loop is HY for Step 1.

Plasma B cells increase what?

The plasma B cell is able to dramatically increase the specificity of the antibodies it produces via processes called somatic hypermutation and affinity maturation § Somatic hypermutation refers to mutation rates in the genes of immunoglobulins that are 1,000,000 times greater than in other cell lines. § This results in affinity maturation, which means antigen-binding regions (Fab) of immunoglobulins (antibodies) are capable of generating increasingly greater affinity for pathogens. § Do not confuse somatic hypermutation and affinity maturation (B cell processes) with V(D)J recombination, which refers to B and T cells early in their maturation process generating antibodies and TCR, respectively, that bear a diverse array of combinations, specificities, and affinities

Can you explain thymus-independent vs thymus-dependent antigens

Thymus-independent means an antigen is not displayed on MHC molecules. Therefore there is no resultant T cell response. Thymus-dependent means an antigen is displayed on MHC molecules. Therefore there is a resultant T cell response. Antigens need to be proteinaceous in order to be displayed on MHC molecules and generate a T cell response. In other words, if a Q asks what kind of molecule could induce a T cell response, choose whatever answer is the protein, even if it sounds weird (e.g., flagellin, or poly-D-glutamic acid capsule of C. anthracis). Lipopolysaccharide (LPS) or the polysaccharide capsule of H. influenzae type B, for instance, are wrong, since they are not protein. If an antigen is not proteinaceous, then it will not be expressed on MHC molecules (i.e., thymus-independent antigen). These antigens therefore require conjugation to a protein so that a T cell response can be elicited. USMLE wants you to know that H. influenzae type B, Strep pneumoniae, N. meningitidis, and typhoid (Salmonella typhi) are conjugate vaccines that are polysaccharide-based (on NBME 27 for Step 1) - i.e., the polysaccharide capsule from these organisms is conjugated to a proteinaceous substrate. Toxoid is the wrong answer for these vaccines. Toxoids are vaccines in which an inactivated toxin from an organism, which is proteinaceous, is administered. Diphtheria and tetanus are classic examples. Thymus-independent response involves an antigen binding to B cell receptor (BCR), followed by the B cell making antibody against the antigen without phagocytosing + expressing it on MHC II to Th2 cells. This process does not result in any type of memory cell being produced, so immunity is short-lived. In contrast, thymus-dependent responses lead to the production of memory cells, so the immunity is longer-lived.

IFN-b

Used between flares of multiple sclerosis (for acute flares gives steroids).

Humoral immunity means

antibodies are involved in the killing of the organism. If antibodies are not involved, then the process does not relate to humoral immunity. § Plasma B cells produce antibody and hence are the main cell of humoral immunity. § B cells are one type of APC that presents antigen to Th2 CD4+ T cells via MHC II. § Th2 cells activate B cells to become plasma cells + induce B cell isotype classswitching via CD40L-CD40 interaction (CD40L on the Th2 cell; CD40 on the B cell). § Therefore B cells and Th2 CD4+ T cells are integral cells in humoral immunity. § USMLE wants you to know that X-linked agammaglobulinemia (XLA) and IgA deficiency are deficiencies of humoral immunity - i.e., the vignette sounds like XLA, but rather than "XLA" as the answer, you will simply select "deficiency of humoral immunity."

C3b and IgG are the immune system's two major opsonins (which means they bind to

antigen and flag it for phagocytosis). § Do not confuse this with IgM and IgG's ability to bind complement. Phagocytes do not have an Fc receptor for IgM, making IgM a poor opsonin. In other words, whilst IgM and IgG bind complement, it is IgG and C3b that are the immune system's major opsonins.

The Th1 and Th2 differentiation pathways

are considered to be in opposition. When one activates, the other is suppressed. IL-12/IFN-γ suppress the Th2 lineage; IL-4 and IL-10 suppress the Th1 lineage. In other words:

Granulomatosis with polyangiitis (Wegener)

c-ANCA; anti-proteinase 3 (PR3); dumb mnemonic I created that helps some of my students: Water Closet (Wegener C-ANCA)

Three main pathways:

classic, alternative, and lectin:

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

p-ANCA (anti-myeloperoxidase)

Microscopic polyangiitis

p-ANCA (anti-myeloperoxidase)

Autoimmune hepatitis

s Anti-smooth muscle

Alternative

triggered by C3b binding directly to the microbial cell surface

Lection

triggered by mannose-binding lectin (a type of carbohydrate-binding protein instrumental in innate immunity) binding to the microbial cell surface

Classic

when complement (C1) binds to the Fc region of IgM and IgG, it flags the antigen bound to the Ab's Fab for opsonization and phagocytosis, or cell death via MAC

Activation of the T cell results in:

§ CD8+ cytotoxic cells directly kill nucleated cells that have antigen loaded on MHC I. § CD4+ T cells are able to exert a variety of effects, depending on their differentiation (discussed below). The activation of the CD4+ T cell usually occurs after its differentiation.