Pathology of Immunity (Part II) Flashcards
Systemic sclerosis (scleroderma) is found to have:
In which organs? (5)
Fibrosis throughout the body.
- Skin*
- GI tract
- Kidneys
- Heart
- Lungs
Systemic sclerosis shows dense collagenous depositions. What are they consistent with?
Subcutaneous fibrosis
What is vascular hyalinization?
A change that occurs to the endothelium in systemic sclerosis.
What is the Raynaud phenomenon?
Progression of systemic sclerosis in the digits. Cold, ischemic fingers become necrotic and the distal phalangeal bone undergoes ischemic resorption.
GI manifestations of systemic sclerosis (2)
Renal vascular disease (1)
Pulmonary manifestations (2)
GI - GERD, esophageal ulceration.
Renal vascular disease - might be associated w/ a life-threatening renal crisis.
Pulm - pulmonary HTN, pulonary fibrosis.
Speckled ANA pattern is in which disease?
What is the Ab used?
Systemic sclerosis.
Ab is anti Scl-70 (anti DNA topoisomerase).
Centromeres in ANA pattern is associated with which disease?
What is the Ab used?
CREST syndrome.
Anticentromere Ab.
What is CREST syndrome?
What are the symptoms?
What is the prognosis?
A unique form of limited sclerosis.
Calcinosis (Ca++ deposits on skin)
Raynaud’s phenomenon
Esophageal dysfunction (reflux and low motility)
Sclerodactyly (thickening and tightneing of skin on fingers/hands)
Telangiectasis (dilation of capillaries causing red marks on skin)
Prognosis is better than systemic sclerosis.
Mixed connective tissue disease’s common presenting feature:
What is in high titer in patients w/ MCTD?
What other diseases does it have components of? (3)
Raynaud phenomenon.
Anti-ribonucleoprotein (RNP).
SLE, systemic sclerosis, polymyositis.
Poorly understood entity.
What is IgG4-related disease?
What types of diseases are involved? (6)
Newly understood pathophysiology tying together many diseases already known about including: AI pancreatitis Riedel thyroiditis Mikulicz's syndrome Ideopathic retroperitoneal fibrosis Inflammatory pseudotumors Inflammatory aortitis
What is the uniting pathophysiology of IgG-4 diseases? (3)
IgG4-producing plasma cells
T cells
Fibrosis
What kind of rejection are B cells involved with? (3)
Hyperacute rejection
Acute Ab-mediated rejection
Ab-mediated rejection
Hyperacute rejection occurs how quickly?
What is it mediated by?
What is an example of it?
What features are characteristic of it?
Minutes to hours.
Mediated by pre-formed Abs.
ABO blood type.
Inflammation followed by thrombotic microvasculopathy.
Acute Ab-mediated rejection is marked by:
Inflammation w/ complement C4d breakdown product.
Chronic Ab-mediated rejection is marked by:
Fibrosis w/ primary effect on vessels.
Acute cellular rejection (T cell mediated) occurs how quickly?
Within days, months or years of transplant.
What is given as an immunosuppressive in transplants?
Corticosteroids
What is given as treatment in T cell-mediated cellular rejection?
Tacrolimus
What is given as treatment in Ab-mediated (humoral) rejection?
Immune globulin
Rituximab (anti CD20 recombinant Ab)
Treatment post transplant can cause problems with immunosuppression. What sorts of infections (4) and tumors (3) can ensue?
Infection - viral (polyomavirus, cytomegalovirus), fungal, bacterial.
Tumors - viral-induced tumors (lymphomas, Kaposi sarcoma), squamous carcinomas.
Why is hematopoietic stem cell transplant needed after transplantation or cancer treatment?
Because ablative chemotherapy and radiation destroys recipient bone marrow.
Graft vs. host disease is ______ mediated.
What are its effects at the skin, liver and intestines?
T cell mediated.
Skin: rash -> desquamation
Liver: jaundice -> cholestasis
Intestines: bloody diarrhea -> strictures
What are 2 examples of secondary (acquired) immunodeficiency syndromes?
Immunosuppression
AIDS
What are 5 examples of primary (genetic) immunodeficiency syndromes?
D/Os of leukocyte function D/Os of complement function D/Os of lymphocyte maturation D/Os of lymphocyte function Immunodeficiencies associted w/ systemic disease
Chediak Higashi syndrome is what type of genetic disorder?
What does not function properly?
What is patients susceptible to?
What is the treatment?
Where can you see the improper function?
AR.
Failure of phagolysosomal fusion.
Bacterial infections.
Fatal w/o stem cell transplant.
Can observe failure of fusion on a peripheral smear.
What are key characteristics of Chediak Higashi syndrome?
Giant granules in neutrophils.
Defects in melanocytes that lead to albinism or grey hair streaks.
Chronic granulomatous disease is defined as a:
What is the mechanism of disease?
Group of genetic disorders.
Failure of superoxide production within phagocytes.
Accumulation of Mo “walls off” infection.
MAC deficiency is noted by deficiency in which complement components?
What infections are common in this disorder?
C5, 6, 7, 8, 9. Any can be affected and not allow for cell lysis.
Neisseria infections (meningitis).
What kind of genetic disorder is hereditary angioedema?
What causes it?
AD.
Deficiency of C1 inhibitor.
Sx of hereditary angioedema (7)
Head sx Throat sx GI sx Bladder/urinary sx Genital swelling Cutaneous edema Swelling of extremities
Lymphocyte maturation disorders are examples of what kind of immunodeficiency?
Primary adaptive immunodeficiency
What is the “common theme” in SCID?
(4)
What are the 2 inheritance patterns?
Deficiency in both B and T cell lineages due to defect in T cell function.
X-linked and AR.
X-linked SCID (4)
Males
Mutation in IL receptors
Low T cell count
B cells present but unable to make Abs because T cells are low.
AR SCID (4)
Adenosine deaminase deficiency
Accumulation of toxic purine metabolites.
T cell formation is blocked.
Some B cell influence, but is hindered by low T cell count.
Tx for SCID (2)
Stem cell transplant
Gene therapy
Cause of DiGeorge syndrome:
What does it effect? (4)
Manifestations? (3)
Low T cell count due to failure of pharyngeal pouches 3 and 4 to develop.
Thymus, parathyroids, heart, great vessels.
Facial/palatal abnormalities, cardiac abnormalities, immune deficiency.
X-linked Agammablobinemia is a defect in:
What does not happen like it should?
What is the risk associated w/ the disease?
BTK (Bruton tyrosine kinase) on the X chr.
Pre-B cells do not mature.
Risk for infection increases after maternal Abs wane, and may present in late childhood as a result.
Agammaglobinemia is associated with which encapsulated bacteria? (5)
It is also associated w/ viruses.
What kind of protozoa? (1)
Steptococcus pneumoniae Haemophilis influenzae type B Streptococcus pyogenes Pseuodomas aeruginosa Staphylococcus
Giardia lamblia
Hyper-IgM syndrome is associated with which infections?
Encapsulated bacteria due to lack of Abs to opsonize.
Hyper-IgM syndrome is associated w/ which mutations?
What is there a lot of? What is there little of?
What is the tx? (2)
CD40/CD40L mutations - interferes w/ T cells helping B cells to class switch.
A lot of IgM, but little of other Igs.
IVIg, stem cell transplantation.
Common variable immunodeficiency (CVID) facts (5)
Class of multiple d/os that result in hypogammaglobinemia.
Most common significant primary immunodeficiency.
Encapsulated bacterial infections are common.
Disease of exclusion.
Later presentation.
Manifestations of CVID (4)
Recurrent sinus and pulm infections.
Granulomas.
Chronic diarrhea - Giardia lamblia.
AI dz - anemia, thrombocytopenia.
IgA deficiency (isolated)
What kind of forms can it occur in?
What does loss of IgA result in? (3)
What else can ensue? (2)
What do these pts. have an anaphylactic reaction to?
Familial and acquired forms.
Sinus and respiratory infections, urinary bladder infections, GI infections.
AI dz and allergies.
RBC transfusion.
Wiscott Aldrich syndrome is what kind of immunological disease?
An immunodeficiency associated w/ systemic disease
Wiscott Aldrich syndrome is a triad of: (3)
What gene is mutated?
Tx?
Thrombocytpenia, eczema, recurrent infections.
WASP gene mutation.
Stem cell transplant.
Ataxia telangiectasia has 3 components. What are they?
What kind of inheritance is it? What gene is mutated? What is defective as a result?
- Neurogenerative disease: ataxia.
- Vascular malformation: telangiectasis.
- Immune deficiency (IgA and IgG) -> respiratory infections, AI dz, cancers.
AR w/ mutation in ATM gene. Defective DNA repair
AIDS vs. HIV
AIDS is the manifestation of what occurs when the HIV affects the body to a degree where immune dysfunction results in:
- Opportunistic infections
- Secondary neoplasms
- Neurologic manifestations
Who is at risk for HIV? (5)
Gays/Bisexuals IV drug users Hemophiliacs Blood recipients Newborns in areas of high female prevalence
How is HIV transmitted to women, usually?
Man + man -> female by breaching the anal or vaginal mucosal barrier introducing the virus in the blood stream or infecting mucosal DCs.
How can HIV be transmitted parenterally?
With IV drugs (most common)
Transfusions (blood is tested, but no test is perfect)
How can HIV be passed from mom to child? (3)
In utero through placenta.
During delivery in contact w/ secretions of birth canal.
After birth w/ ingestion of breast milk.
What kind of virus is HIV?
Retrovirus of Lentivirus family
Capsid protein of HIV-1
p24 - it can be tested for.
Glycoproteins of HIV-1 (2)
What is the clinical importance of them?
gp120 and gp41.
They are good for attachment, so they are good drug/vaccine targets.
Viral enzymes of HIV-1 (3)
Protease
Reverse transcriptase
Integrase
What are the 3 retroviral genes in the HIV-1 genome?
gag, pol, env.
What do the following DNA regions do in HIV-1?
LTR:
gag:
env:
pol:
LTR: initiates transcription and binds TFs.
gag: encodes for proteins inside the virus.
env: encodes for surface glycoproteins.
pol: encodes for viral enzymes.
How does HIV enter a cell? (3)
- HIV uses a CD4 molecule for a receptor along with co-receptors for chemokines (CCR5, CXCR4).
- gp120 binding to CD4 allows secondary binding to co-receptor.
- gp41 can now use the fusion peptide to drill into the host target cell membrane and insert its genome.
How is HIV replicated once inside the cell?
- Reverse transcriptase makes proviral DS DNA from original RNA genome.
- Integrase inserts provial DNA sequence into host genome.
- Host cell activation occurs and triggers LTR to initiate transcription of the HIV viral RNA.
What molecule is release once there is antigenic stimulation in HIV?
What happens?
NF-kB.
It is supposed to upregulate the T cell response, but it actually initiates viral transcription through the LTR.
What is the direct cytopathic effect?
When viral replication inside the cell causes host cell death.
In what other cells (other than CD4+ T cells) does HIV infect? (3)
Mo
DCs
Microglia
What happens to the B cells in HIV? (4)
- Proliferative response
- Might become clonal -> lymphoma.
- Nonspecific hypergammaglobinemia.
- Impaired humoral immunity.
Where does viral replication occur in HIV?
LNs
How many days after exposure does viremia occur in HIV?
WHat about seroconversion?
7-14 days
7-21 days, 95% by 4 wks.
What are the first, second and third Abs to test positive in HIV?
First - viral RNA (nucleis acid test (NAT))
Second - protein Ag p24.
Third - Ab to HIV
How can blood that has been tested still contain HIV?
Because it tests w/ NAT which is the earliest way to detect HIV. It allows a 7-14 day period after exposure to exist prior to being positive on a test.
Sx of acute retroviral syndrome (3)
Fever, sore throat, muscle aches.
Self-limited.
What is the viral set point?
What may it predict?
End of initial viremic spike.
May predict CD4 cell loss.
What is seen in the period of clinical latency in HIV?
It is a period of “silent massacre” of CD4 cells.
May last years w/o sx.
What are the 2 major components of diagnosing AIDS?
- Declining CD4+ counts.
2. Onset of opportunistic infection or neoplasm.
Pneumocystis jiroveci
Opportunistic fungal infection
AIDS-defining illness.
Can be diffuse, or focal, or anywhere radiographically.
Which agents could cause diarrhea in AIDS patients? (5)
Protozoa Bacteria Viral Mycobacterium Fungi
Kaposi sarcoma
What virus is associated w/ it?
Vascular tumor.
Human herpesvirus 8 (KS herpesvirus).
AKA Castleman’s disease.
Amyloidosis
Abnormal folding of proteins
Acquired mutations can cause amyloidosis how? (4)
B cell proliferation -> plasma cells -> immunoglobulin light chains -> AL protein (due to limited proteolysis)
Chronic inflammation can lead to amyloidosis how?
Mo activation -> IL-1 and IL-6 -> act on liver cells -> SAA protein -> AA protein (due to limited proteolysis)
AL is associated with:
AA is associated with:
Light chain diseases
Amyloid-associated diseases
Where do amyloids tend to manifest? (5)
Kidneys Liver Heart Brain Fat pads (can be used to dx if systemic)
Initial presentation of amyloidosis in kidney:
Heart:
Proteinuria -> edema
Dysrhythmias
Which stain is used to visualize amyloids?
Congo red stain will show a “apple green” appearnce of the amyloid under polarized light.
If AIDS is found early, what do we do?
- begin highly active anti-retroviral therapy (HAART)
- CD4+ counts monitored and adjusted as needed
- prophylactic abx against infection
- disease may progress despite therapy, but usually it is fairly successful
- if not treated, the disease will progress to opportunistic infections and neoplasms
What is a sign of AIDS in a brain CT?
CNS toxoplasmosis
Which major pathogen caused diarrhea in AIDS patients?
What is the historical side note of this pathogen?
Protozoa Cryptosporidium
In 1993, this pathogen was found in potable water and infected 400k people and the death rates for AIDS patients was significant greater
What virus can cause AIDS-related lymphomas?
Re-activation of latent Epstein Barr virus by stimulating germinal centers to produce huge amounts of B cells
What STI-related cancer can accompany AIDS?
Cervical cancer from HPV infection
