WHIYFW - aka basic pathophys

Question 1

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

StAR

Answer 1

Steroid Acute Regulatory Protein - Rate limiting step for steroid hormone biosynthesis, and regulated by ACTH. K/O (Addison’s, e.g.): panunderproduction of steroid hormones (including aldosterone?). Overactivity: Cushing’s syndrome due to massive overproduction of steroids (remember cortisol mediates most of the effects of Cushing’s)

Question 2

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

Cyp21A2 / 21-α hydroxylase

Answer 2

The enzyme in adrenal zona glomerulosa and zona fasciculata that converts progesterone to 11-DOC, and 17(OH)-progesterone to 11-deoxycortisol, respectively

Deficiency causes both of these pathways to be blocked (cannot progress to synthesize aldosterone or cortisol); all precursors shunted to DHEA pathway (zona reticularis); ALSO, ACTH with no negative feedback from cortisol is stimulating several of the earlier enzymes in the steroid biosynthetic pathway.

Clinical syndrome: Most common cause of congenital adrenal hyperplasia (CAH).

Phenotype: virilization, ambiguous genitalia at birth, sodium loss (with hypotension and high plasma renin as a result), hyperkalemia, high ACTH.

Question 3

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

Cyp11B1 / 11-hydroxylase

Answer 3

The enzyme in adrenal zona fasciculata that converts 11-deoxycortisol to cortisol

Deficiency causes increase in aldosterone precursors (and presumably cortisol precursors too), especially 11-DOC, which can activate MRs, and increased androgens due to shunting of precursors

Clinical syndrome: Second common cause of congenital adrenal hyperplasia (CAH).

Phenotype: HTN due to excess 11-DOC, hypokalemia, low aldosterone (remember not part of an axis; release linked only to blood volume) and high ACTA (lack of negative feedback from cortisol)

Question 4

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

Cyp17 / 17α hydroxylase

Answer 4

The enzyme in adrenal zona fasciculata and zona reticularis that hydroxylates the 17-carbon of progesterone and pregnenolone, respectively (z. reticularis lacks the enzyme to convert pregnenolone to progesterone)

Deficiency causes both of these pathways to be blocked; cannot synthesize cortisol at all. Androgen production will be reduced (remember gonads of both sexes produce some androgens)

Clinical syndrome:

Phenotype: HTN with hypokalemia (low aldosterone but high MR activity from 11-DOC); high ACTH (no cortisol); feminization/pseudohermaphroditism (underproduction of of androgens)

Question 5

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

Classical Complement Pathway

Answer 5

(C1, C2, C4)

Deficiency leads to immune complex disease due to poor clearance of immune complexes

(Remember the immune complex is the Ab bound pathogen - but you need C3b to clear it)

Question 6

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

MBL

Answer 6

Mannan binding lectin, part of lectin pathway of complement activation

Deficiency leads to bacterial infections, mainly in childhood (classical pathway takes over as you grow)

Probably specifically gram negatives

Question 7

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

Alternative Complement Pathway

Answer 7

Deficiency in Factor D/Factor P(properdin) leads to infection with pyogenic bacteria and Neisseria spp but NOT immune complex disease

Question 8

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

C3

Answer 8

Deficiency leads to infection with pyogenic bacteria and Neisseria spp.

Some immune complex disease

(Combination of classical/lectin pathway)

Question 9

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

MAC components

Answer 9

C5-9

Deficiency leads to infection with Neisseria spp. only

Question 10

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

C1INH

Answer 10

C1 inhibitor

Failure to regulate C1 results in fluid accumulation and epiglottal swelling, “abdominal attacks?”

Hereditary angioneurotic edema.

Acute attacks may be treated with C1INH concentrate

Question 11

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

CD59

Answer 11

CD59 inhibits formation of the MAC in the common pathway of complement activation

Lack of regulation of the pathway leads to RBC lysis

Paroxysmal nocturnal hemoglobinurea.

Question 12

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

IgA

Answer 12

Selective IgA deficiency is the most common primary immune deficiency

Interferes with mucosal immunity and there will be low/absent serum IgA (though there may be compensation in many individuals by IgM). Many patients will not be any more susceptible to infection

HOWEVER, suspect it if: (1) family history of IgA deficiency/agammaglobulinemia; (2) high incidence of oral infections; (3) frequent respiratory infections; (4) chronic diarrhea

Question 13

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

MHC - II

Answer 13

Major histocompatibility molecule, class II

Normally used by APC’s (DC’s, M/M’s, BC’s) to present antigen

Without it, unable to stimulate response from TC’s for sure - could get some response from B’s but it wil be impaired by lack of signaling from other APC’s to stimulate T’s

Bare Lymphocyte Syndrome

Question 14

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

MHC-I

Answer 14

major histocompatibility complex, class I

normally presents self-antigen; present on ALL nucleated cells

if can’t present self (and therefore not internal non-self pathogenic) peptides, first and foremost won’t be able to create CD8 TC’s! - impaired TMMI, perhaps increased cytotoxicity from NK’s?, increased CD4/BC reactions (no CD8’s to regulate)

susceptibility to infection.

Question 15

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

thymus

Answer 15

absent thymus: (plenty of TC progenitors but) absolutely no mature T cell activity

severe immunodeficiency; recurrent infection

DiGeorge Syndrome / Velo-Cardio-Facial Syndrome two presentations, caused by a large deletion on chromosome 22

Transplantation of an allogenic thymus graft into patients with DGS rescues the TC deficiency

Question 16

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

FOXN1

Answer 16

FOXN1 codes for, among other things, a transcription factor essential for functional thymic epithelial cells (also hair)

SNP of this gene (chromosome 17) changes CGA→TGA (stop codon); you get cyst-like structures instead of TEC’s

no immature HSC’s recruited; no T cell maturation

thymic implant can restore TC immune response in these patients

Question 17

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

AIRE

Answer 17

Auto Immune Regulator Element gene - allows TEC’s to express peripheral, esp. endocrine, self-proteins for negative selection of DP T lymphocytes: Failure of central tolerance

mutations in the gene result in APECED:

autoimmune polyendocrinopathy candidiasis ectodermal dystrophy

affected organs include adrenal, thyroid, parathyroid, pancreas

Question 18

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

FOXP3

Answer 18

signature gene of Tregs; expression required in CD4+ TC’s to induce Treg phenotype: failure of peripheral tolerance

k/o (Xp11.23-Xq13.3), get IPEX:

immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance

you get multisystem autoimmune disease. common symptoms: diarrhea (Tregs super important in gut), DM-I, thyroid disorders, eczema

Question 19

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

Too much Ab already present at the time of a vaccination

Answer 19

Arthus rxn. Hypersensitivity type III (Localized)

Because Ab already exists to vaccine, immune complexes form at a rate that overwhelms the RBC transport/clearance system. Massive neutrophil activation occurs at the site [IL-8 + vasoactive mediators], and you get swelling, redness, pain.

BUT NO INFECTION!

Question 20

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

Immune reaction to a foreign serum protein

Answer 20

Acute serum sickness. Type III hypersensitivity rxn.

May occur after injection of an antivenom, for example. Immune system activated (Th2) against foreign protein. During the time that the foreign protein is being cleared, the rate of immune complex formation exceeds the clearance capacity of the liver. Symptoms depend on location of IC deposition, but may include synovium [arthritis], skin [rash, itching, tissue destruction], kidney [loss of function, tissue destruction]

IF CAUSED BY INFECTION - source control is key

Question 21

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

Rh positive fetus / Rh negative mother

Answer 21

Rh antigen expressed in dominant manner. Mom exposed to fetal RBC during delivery, becomes sensitized & produces anti-Rh Ab [or at least BC’s to produce it at next sight].

If next baby is Rh(+), Mom forms anti-Rh IgG which can cross the placenta and destroy fetal RBC’s

Treatment: High levels of anti-Rh IgG during pregnancy [in a way that prevents transfer across placenta] and within 72h postpartum activates Fcg ITIM receptor such that BC’s are made quiescent. CD4T/B memory T’s not formed.

Note: IgM does NOT work!!

Question 22

Identify the function of the named protein/pathway/etc. and what happens when its activity is either increased or decreased. Include name for clinical syndrome if applicable.

TLR-5

Answer 22

In mice, TLR-5 KO induces obesity