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Flashcards in Block 1 Disease Deck (85)
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1

Ginigivitis and internal ulcering

Given as examples of what could happen with a deficiency in innate immunity; other scenarios given = you can have absence of appropriate leukocyte migration (lack of chemokine attractants); you also might be able to get the leukocytes to the site of invasion but cannot effectively kill

2

Severe Combined Immunodeficiency (SCID)

David the Bubble Boy, lived in a sterile chamber for 12 years; could not make B and T cells; X-linked recessive; Bone marrow transplant is treatment; common gamma chain deficiency; Gamma is in the signaling subunit of the receptors for several cytokines, including IL-2, 4, 7, 9, 15 and 21. When the gamma chain is not functional, immature lymphocytes cannot proliferate in response to IL-7, which is the major growth factor for these cells. Contrast this with Autosomal SCID (ADA deficiency), page 227.

3

Gout

Deficiency in innate immunity; PRRs recognize endogenous (host-derived) molecule uric acid, which leads to inflammation, inflammasome activation

4

Lupus

Deficiency at the level of adaptive immunity; see lecture 14's SLE explanation

5

MS

Deficiency in adaptive immunity- adaptive immune response against self antigens

6

Deficiency in epithelial sloughing

Some microbes have increased capacity for colonization, adherence. If you don't have sloughing off mechanisms (like in vaginal epithelium), you are more susceptible to certain infections; see Neisseria Gonorrhoeae (lecture 3)

7

Chronis Bronchiolitis

Smoking leads to torching of epithelial cilia

8

Cystic Fibrosis

Dehydrated mucous gets trapped, allowing for increased susceptibility of microbes for taking up residence in the lung

9

Crohn's Disease

Pathogens in the gut are especially problematic when there is significant damage to the epithelial lining, as seen in Crohn's Disease (see CC-02 notes below for more on Crohn's Disease)

10

Respiratory Syncytial Virus

In the case of RSV, you can give macrophages which can be alternatively activated (differentiation to M2 state)-- confers protection against the lung damage which would normally occur in such an infection (BUT, also confers asthmatic-type reaction with alternative activation macrophage pathway, not just wound repair)

11

Alzheimer's

When B-amyloid aggregates in the brain, as in Alzheimer's, can be seen by the immune system as a danger associated molecular pattern, or DAMP, and lead to inflammation

12

Gram negative sepsis

Dysregulated production of pro-inflammatory cytokines ("cytokine storm"), ROS, lipid metabolites , bystander cell damage produces DAMPs which feed back on the macrophages to produce even more cytokines and dysregulation

13

NADPH-Oxidase Deficiency; Chronic Granulomatous Disease (CGD)

Cannot convert oxygen to superoxide anion, which leads to recurrent bacterial infection (ROS is a potent microbicidal agent that aids lysosomes when lysosomal destruction is not sufficent); important to know that MPO deficiency, though also leading to lower levels of free radicals, isn't as severe (MPO is more downstream in the pathway on slide 67); also important to know that deficiencies in any of the enzymes of the COUPLED reactions (i.e. Glutathione reductase) will have phenotype similar to that of NADPH Oxidase deficiency (CGD)

14

Chediak-Higashi Syndrome

Abnormal fusion of phagosomes with lysosomes. Failure to kill ingested microbes; impaired myeloperoxidase also presented in the context of a decreased ability for CD8 cells to KILL. From the book "AR immunodeficiency disease due to a defect in cytoplasmic granules of various cell types that 1. affects the LYSOSOMES of macrophages and neutrophils and 2. affects the granules of CD8 cells and NK cells. Patients show reduced resistance to infections with pyogenic (pus-causing) bacteria.

15

Leukocyte Adhesion Deficiency (LAD)

Leukocytes can't bind to endothelium and thus, they cannot diapedese. Due to AR mutation that results in faulty expression of CD18 (CD11a/CD18 and CD11b/CD18) are present on neutrophils and monocytes and are pivotal to attachment to endothelium for diapedesis into the tissues

16

Complement System Abnormalities

Example is a C8 deficiency; increased frequency of Neisseria infection, no formation of the MAC (this is always asked about on board exams)

17

IRAK4 deficiency

Defect in a key enzyme in TLR signaling (the first enzyme that is recruited to MyD88) in recurrent bacterial infections (mostly Gram +) Block the signaling pathway (#1) that leads to NFKB

18

TLR polymorphisms

Example (TLR4), increased sensitivity to certain infections

19

Pneumococcus

Resistance to phagocytosis; capsular polysaccharide inhibits phagocytosis; lots of serotypes prevent vaccine development

20

Staphylococci

Resistance to ROS in phagocytes; production of catalase by staph breaks down reactive oxygen intermediates

21

Neisseria meningitides

Resistance to complement activation (alternative pathway); Sialic acid expression inhibits C3 and C5 convertases

22

Streptococcus

Streptococcus is gram positive and its outer surface is peptidoglycan (recognized by TLR2). Resistance to complement activation (alternative pathway); M protein blocks C3 binding to organism and C3b binding to complement receptors; How do you make a streptococcus pneumoniae conjugate vaccine? (Lecture 5, slide 31)

23

Pseudomonas

Resistance to antimicrobial peptide antibiotics; synthesis of modified LPS that resists action of peptide antibiotics

24

Neisseria gonorrhoeae

Prevent cell sloughing; increase adhesion molecules on vaginal epithelial cels-- decreases sloughing, Neisseria is an encapsulated bacteria (C' is important for defense, especially MAC, so we must vaccinate C'-suppressed folks)

25

Paroxysmal Nocturnal Hemoglobinuria

CD59, CD55, and GPI Deficiencies. CD59 (or protectin) inhibits formation of the MAC on autologous or allogenic cells (widely expressed on membranes)

26

Hereditary Angioneurotic Edema HA(N)E

C1 INH Deficiency

27

Candida

Yeast, attract factor H to their surface, so complement cannot be activated

28

Helicobacter

Usually destroyed by the lytic cascade; CD59 (the molecule that inhibits MAC formation) can be incorporated into the bug

29

Leishmania

Leishmania will actually use iC3b to its advantage. Phagocyte will take up parasite; then Leishmania will inhibit phagosome-lysosome fusion. Uses complement system to its advantage.

30

Hypersensitivity reaction to allergens

IgE reaction: sets off FC epsilon receptor chain of events (on mast cells and eosinophils) leading to granule release. The same thing occurs (normally) as a reaction to helminths, or worms

31

Polio

The oral attenuated polio virus functions in neutraliization of the virus by mucosal IgA antibody

32

Tetanus, diphtheria

The toxoid vaccine: functions by neutralizatoion of toxin by systemic IgG antibody

33

Hepatitis, A or B

The recombinant viral envelope proteins in vaccine: function to induce neutralization of virus by systemic IgG antibody

34

Pneumococcal pneumonia, haemophilus

Conjugate vaccines (composed of bacterial capsular polysaccharide and protein) work by promoting opsonization and phagocytosis mediated by IgM and IgG antibodies, directly or secondary to complement activation

35

Omenn Syndrome

Rag- 1 mutatuons affect RSS DNA binding or catalytic activity. Rag-2 mutations (sometimes in plant homeodomain) affect chromatin accessibility of VDJ recombinase. A form of severe combined immunodeficiency (SCID) in which symptoms present like allergic hyperreacivity; basis for the disease is deficiency in RAG-1 or RAG-2 recombination activating proteins (RAG-2: mostly defects in the PHD region which locates methylated accessible H3 to which RAG-1 can bind). Some B and T Lymphocyte apparently remains because you see elevated (paradoxical) IgE, eosinophilia; Theory is that TH2 cells remain and promote differentiation to IgE. Treatment = bone marrow transplantation, gene therapy; Symptoms = erythroderma, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy

36

SCID + radiation sensitivity

Artemis= nuclease which cleaves the hairpin (defect in NHEJ); Ligase 4 = Rejoins the DNA (also a defect in NHEJ); Defects in these? Patients have SCID but also radiation sensitivity, genomic instability, no T/B cells, adult-onset immunodeficiency, childhood EBV/lymphoma; Treatment = Bone Marrow Transplantation

37

Type 2 Hyper IgM Syndrome

Autosomal- mutations in the AID genes; not able to mount Ab responses with isotypes other than IgM (primary isotypes) (aka hyper IgM syndrome) Recurrent bacterial infection, pneumonia, will have same infections over and over; CANNOT PRODUCE HIGH INFINITY ANTIBODIES; will have ENLARGED GERMINAL CENTERS-- because AID cannot mutate and move the B cells onto becoming long-lived

38

Type 1 Hyper IgM Syndrome

X-linked or auto- CD40 or CD40L gene mutations (one of the ligands on T cells which interact with CD4 T cells and B cells; essential to induce AID expression (SHM and Class-switching) -- you have similar phenotype to Type 2 *Be careful about the differences here* Difference noted on slide is that you will not see CD40L on T cells, patients susceptible to pneumocystis infection; there will be NO GERMINAL CENTER FORMATION

39

Lymphoid Malignancies

VDJ recombination and class switching mutations can lead to chromosome translocations and lymphoid malignancies (Non-Hodgkin's Lymphoma is an example)

40

Atypical Hemolytic Uremic Syndrome

Caused by Factor I, H or CD46 deficiency (usually), also can be caused by GOF mutation in Factor B or C3. Can develop in infancy or adulthood. You need some environmental trigger (infection, Rx, surgical procedures, pregnancy) to cause initial injury to lining of blood vessions. Unregulated complement cascade = MAC damage

41

Insulin Dependent Diabetes Mellitus

RR=14 for showing IDDM phenotype if possess HLA Allotype DQ8 and DQ2; heterozygous heterodimer strongly associated with increased suscpetibility to diabetes

42

Ankylosing Spondylitis

B27 HLA allotype (Class I MHC) RR>150 for developing this disease; AS is an autoimmune disease than affects the spine; MRI and X-ray studies of the spine show characteristic spinal and sacral region changes, fusions. What initiates ankylosing spondolytis? There are antigen-dependent theories and antigen-independent theories

43

IBD

IRRITABLE BOWEL DISEASE: means ulcerative collitis and Crohn's Disease, most often considered a disease of the young (20-30s)

44

Ulcerative Colitis (one subset of IBD)

Colon only, superficial musocal inflammation, continuous distribution, rectal involvement, STARK contrast

45

Crohn's Disease (another subset of IBD)

Challenging to distinguish between Crohn's and Ulcerative colitis but Crohn's can occur anywhere in the digestive tract (most commonly small intestine but can be anywhere, from mouth to anus), more often right sided pain (as opposed to L-sided pain in ulcerative colitis), chronic inflammatory procress- you might see strictures (narrowing of the lumen due to scarring), can use an antiinflammatory medication like a monoclonal Ab; fistulization is possible (abnormal connections between different parts of the bowel); granuloma on bx is pathognomonic for Crohn's

46

Toxic Shock Syndrome

Presented in the context of superantigens; viruses and bacteria make molecules which bind both the TCR and MHC Class II molecule; bridge these two (without peptide specificity) and can result in general T cell activation, for any T cell bearing the particular Vbeta. Cytokines are building up in the blood and totally throw off homeostasis; can't make a specific response to the pathogen.

47

TAP mutation

If there in an error in TAP, then processed peptides cannot be loaded into Class I MHC molecules. Thus, no peptide at surface = unstable class I (degraded quickly)

48

HSV1

Blocks peptide binding to TAP

49

HCMV

Inhibits TAP ATPase activity and blocks peptide release into endoplasmic reticulum, blocks tapasin function, transports some newly synthesizes MHC class I molecules into cytosol

50

Bovine herpes virus

Inhibits TAP Peptide transport

51

Adenovirus

Competitive inhibitor of tapasin (retention of MHC Class I in the endoplasmic reticulum)

52

Murine gamma herpes virus

E3-ubiquitin ligase activity (degradation of MHC class I)

53

Murine CMV

Interfered with recognition by cytotoxic T lymphocytes by unknown mechanism

54

Class II Molecule deficiency (rare)

There are transciption factors that are specific for all of the MHC Class II molecules (DP, DQ, DR), so if one is missing, there can be blockage of all Class II molecules at the surface; when Class II is missing, you don't see CD4 cells.

55

Class I Molecule deficiency (rare)

Possible in the setting of a TAP mutation, B2 microglobulin mutation, Tapasin mutation; when Class I is absent from the cell surface, you see no CD8 cells.

56

Coeliac Disease

Gliadin is transported across the IECs; gliadin gets modified by transglutaminase; makes ionic bonds with groove of the DQ2 and stimulates cytokine release and subsequent damage to intestinal epithelium (If you have DQ2 Class II molecule, best to avoid foods with gliadin in it.) MHC alleles are also associated with Rheumatoid arthritis, Type I DM.

57

Myeloma

Dr. Rapoport's study re: TCR genes specific for HLA-A02 bound to a myeloma-specific antigen: transfection into patient T cells and infusion into patient-- looked at T cell persistence and function (using TAP-negative cells); disappearance of myeloma cells in the bone marrow

58

T-ALL

Chromosome translocations and activating point mutations of Notch-1 are frequently found in T-ALL (Notch-1 interacts with a thymid epithelial cell in the thymus to promote differentiation in the T cell ineage)

59

B-ALL

Chromosome translocations and point mutations that disable Pax-5 and EBF are found frequently in B-ALL

60

ADA-Deficiency

ADA is an enzyme involved in lymphocyte development; if deficient, metabolites accumulate inside of the cell (toxic)

61

RAG-deficiency

Rag enzymes responsible for VDJ recombination in early lymphocytes; without recombination, will not see mature B and T cells

62

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED)

Human AIRE mutation (autoimmune regulator)-- this is the transcription factor responsible for many (but not all) ectopic self antigens in thymic medulla

63

Scurfin Mutation

X-linked; not discussed in lecture, presented on the slide in the context of FoxP3

64

IPEX

Immune dysfunction polyendocrinopathy enteropathy X-linked syndrome (IPEX) Not discussed in lecture, on slide only

65

Human Fox P3 Mutation

IBD, Type I DM, Eczema; Foxp3 is the transcription factor associated with Tregs and carrying out of their effector function (regulation of the immune response, production of TGFbeta and IL-10)

66

Human Autoimmune Lymphoproliferative Syndrome (ALPS)

A defect in the AICD system; FasL is an important ligand expressed after T cells are activated; FasL binds Fas receptor on other T cells; Fas trimerization leads to downstream activation of caspases, cleavage of nuclear DNA and eventually apoptosis. This is highly important for negative T cell regulation. A defect in Fas will lead to ALPS. Recall that FasL (on T cells) also binds Fas on target cells in the context of signalling for apoptosis of such target cells

67

Hemophagocytic lymphohistiocytosis (HLH)

Genetic or acquired. Associated with mutations in pathways controlling granule exocytosis OR actual mutations in the perforin molecule itself. Aborted ability of these CD8 cells to kill their target cell. Get "revved" up/activated but can't do granule exocytosis to induce apoptosis. BUT can still secrete pro-inflammatory cytokines like IFN-gamma therefore you get angry macrophages (the hemophagocytosis part). Lab values show high levels of these pro inflamm cytokines and patient likely to have fever. New drug in Europe that is anti-IFNgamma antibody to neutralize all that excessive IFNgamma these patients make. Reverses the toxicity associated with the disease.

68

Listeria, Mycobacteria, Viruses, Cryptococcus, Rickettsia

All are examples of typical intracelular pathogens which would call for a CD4 TH1 response (by IFN-gamma and IL-12 in the environment of naive T cells. TH1 cells produce IFN gamma to enhance macrophage killing and

69

Staphylococcus, Helminths and Clostridium

Typical extracellular pathogens; will call for a TH2 response (production of cytokines that promote B cells (Ab responses) and eosinophil (allergy/anti-helmith) function

70

Klebsiella, S. aureus, fungi

Typical etracelular pathogens which will call for a TH17 response and production of IL-17; will activate epithelial cells and INDIRECTLY activate neutrophils

71

Job's Syndrome (Hyper IgE Syndrome)

Mutations in STAT3 lead to defects in IL-6 signaling and the TH17 lineage (because IL-6 needed for promotion of differentiation of naive T cells to TH17); a rare primary immunodeficiency disease characterized by recurrent stahylococcal skin abscesses, recurrent fungal lung infections (candida), eosinophilia and high serum levels of IgE

72

HHV-3

Herpes virus, shingles; as you age, the T cell responsiveness fades (memory T cell responses are not strong, numerous enough to keep virus in check so high likelihood for shingles virus exists)

73

Influenza

H1N1 epidemic; antigenic shifts and drifts

74

Vitamin D Deficiency

Often reported in patients with IBD and colitis; Vitamin D (like Vitamin A) required to maintain intestinal homeostasis, stabilize tight junctions, modulate TCR, decrease proinflammatory cytokines, increase Tregs, and maintain self-tolerance

75

Poliovirus, cholera, rotavirus and influenza

Examples of mucosal vaccines (live attenuated is best method for promotion of immune response)

76

SLE

Systemic Lupus Erythematosus- think defect in the germinal center reaction. For possible treatment option, see IV Ig on "Drugs" sheet.

77

NK Cell Deficiency

There is no congenital deficiency specific to NK cells; this tells us that they are doing something very important. In mouse experiment with no NK cells and viral infection, mice die (adaptive immune response takes too long).

78

Rheumatoid Arthritis

Different from osteoarthritis in that osteoarthritis is bone on bone; RA is inflammation within the synovial membrane (infiltration of white cells into synovial fluid). TNF-alpha and IL-1 are central mediators [see chart on slide 23]: Downstream effects of production of Abs, locally and systemically, collagenase, macrophage activation (and whole process is amplified again and again). Psoriatic arthritis is TNF-dependent, also, so the drug is marketed for this as well.

79

Muckle Wells Syndrome

Inflammatory disease, Point mutation in NLRP3 (NALP3), which is upstream of caspase 1 activation. This is a GOF mutation in which too much IL-1B is released into circulation. Moderate low grade fevers, starting in infancy, progressive hearing loss, joint pains, one of a group of related diseases called CAPS, or cryopyrin associated periodic syndromes.

80

COPD

Associated with IL-17

81

DIC

Can occur in the context of septic shock and too much TNF-alpha being produced (thrombus formation and low resistance)

82

Hypoglycemia

In the liver, too much TNF will act to antagonize gluconeogenesis

83

Latent TB

You should not use a TNF antagonist, such as Enbrel (entanercept) in this case, because you need TNF to prevent reactivation of the TB

84

Chronic Inflammatory Diseases- Loss of control of IL-1Beta secretion

Normally, inflammasome activates caspase 1, allowing cleavage of the pro-form of IL-1Beta into its active form. Hereditary diseases of the inflammasome = loss of control of the above normal function. Excessive IL-1Beta secretion. Examples include: refractory gout attacks, post-MI remodeling, decompensated heart failure, glycemic control in Type II DM, insulin resistance in Type I DM, Dry eye disease, Autoimmune hearing loss. All benefit from IL-1 blocking therapies

85

SARS

Severe acute respiratory syndrome (coronavirus), treatment with interferon alpha