Diseases of Immunity Flashcards
What is central tolerance and where does it occur?
it is learned tolerance prior to release from generative organs; occurs in the thymus and in the bone marrow
What happens if B cells recognize and react to their own self antigens?
they have the opportunity for receptor editing or they undergo apoptosis
What are the mechanisms of peripheral tolerance?
T regulatory suppression and anergy
How does anergy occur?
T lymphocytes have inhibitory receptors; our self cells express ligands and if the T cells bind to these ligands on the self cell they undergo anergy
what are the inhibitory receptors that are found on T lymphocytes that are important in the process of anergy?
CTLA and PD-1
what do our self cells express that can bind to the T lymphocytes and induce anergy?
CD 80/86 or PDL1
What are three different mechanisms for autoimmune diseases?
susceptibility genes, molecular mimicry, and epitope spreading
what autoimmune diseases occur via the mechanism of susceptibility genes?
ankylosing spondylitis, rheumatoid arthritis, and Crohn’s disease
what autoimmune diseases occur via the mechanism of molecular mimicry?
rheumatic heart disease
what autoimmune diseases occur via the mechanism of epitope spreading?
oral lichen planus
What is the susceptible gene that is associated with ankylosing spondylitis?
B27
what is ankylosing spondylitis/ how does it present?
it is a hereditary inflammatory condition of the joints; young patients present with severe neck and back pain; bamboo spine
What is the susceptible gene associated with rheumatoid arthritis?
PTPN22 (protein tyrosine phosphatase)
what does the polymorphism of the PTPN22 gene lead to?
there is not adequate elimination of the self reactive clones, so you don’t suppress your T cell response; leads to increased inflammation; they have a direct influence on reducing B-cell and T-cell tolerance
What is the susceptible gene associated with Crohn’s disease?
NOD-2 gene
what happens in cases of polymorphisms of the NOD-2 gene?
paneth cells in the intestinal epithelium are ineffective at killing microbes; so there is a significant overgrowth of bacteria and an accompanying inflammatory response
what is molecular mimicry?
when there is antigenic similarity between true pathogens and native tissues leading to autoimmunity
What is the mechanism of rheumatic heart disease?
molecular mimicry
What occurs during epitope spreading?
some of our antigens are hiding intracellularly or they are just anatomically hidden; this means that if something happens to breakdown the intact structures or cells, we can spill out antigens that our immune system has never seen before
during oral lichen planus, what happens during the initial T response?
leads to keratotic lesions in the oral and conjunctival mucosa, which leads to basement membrane disruption exposing antigenic proteins (lichen planus)
what is the secondary disease that follows Lichen Planus?
Pemphigoid (a secondary B cell response)
If you suspect an autoimmune disease might be occurring in your patient, what would be one of the first test you order?
ANA (anti-nuclear antibody) test
if a patient tests positive for ANA, what test would you look for to be positive if they had lupus?
anti DS DNA or anti smith
if a patient tests positive for ANA, what test would you look for to be positive if they had Sjogren syndrome?
Anti Ro/ SS-A or Anti La/ SS-B
if a patient tests positive for ANA, what test would you look for to be positive if they had systemic sclerosis?
Anti DNA topoisomerase (Scl-70)
what is the staining pattern associated with systemic lupus erythematous?
homogenous
what is the staining pattern associated with systemic sclerosis?
nucleolar (or speckled)
what is the staining pattern associated with CREST syndrome?
centromeric
what is the genetic association with Lupus?
family patterns or HLA-DQ possibly
what is the gender bias associated with lupus?
females get it more often than males
what environmental factor is associated with increased risk of developing lupus?
UV radiation
there are multiple immune mechanisms involved in systemic lupus erythematous, what are 2 examples?
B cells and CD-4 T cells, and immune complex formation (TYPE III HYPERSENSITIVITY)
what is the most sensitive/consistent thing you are going to see present in patients with lupus?
an abnormal CBC (could be a hemolytic anemia, thrombocytopenia, or leukopenia
What is the most common pattern of lupus nephritis?
diffuse lupus nephritis (class IV)
how do patients with diffuse lupus nephritis typically present? and why?
they present with complaints of proteinuria and hematuria; the immune complexes have landed in the glomerular capillary loop
how can you identify diffuse lupus nephritis on a regular microscope?
the mesangial cells are proliferating as the damage is occurring there; the glomeruli show increased cellularity
what does immunofluorescence of diffuse lupus nephritis show?
a granular pattern of IgG antibody-containing complexes ; tends to give a very patchy appearance
what is a cardiac complication associated with lupus?
Libman-Sacks endocarditis and CAD
what is libman-sacks endocarditis?
verrucous (warty) valve deposits compromised of fibrin; these are not infective and they can rarely embolize
what might cause lupus patients to be more susceptible for CAD?
the contribution from anti-phospholipid antibody syndrome
What histological feature is always associated with Lupus and what is this?
an L-E cell; what happens in lupus is your phagocytic cells (e.g. neutrophils) find damaged cells and swallow them; the neutrophils become so full that it had to squash its own nucleus
What is discoid lupus?/ how does discoid lupus present
discoid rashes on face and scalp; these patients don’t tend to have renal involvement or cardiac involvement; just the skin involvement
why is discoid lupus hard to make a diagnosis?
these patients often times do not have a positive ANA test and when they are positive they do not have specific markers
what is drug-induced lupus/ how does it present?
a very specific scenario; an older, cardiac patient that you put on a new drug and then they develop lupus; it is a medication induced breakdown of self-tolerance; they have arthralgia, fever, and cutaneous lesions
what do patients with drug-induced lupus test positive for?
ANA and anti-histone antibodies
what is sjogren syndrome?
an autoimmune disease resulting in the destruction of lacrimal and salivary gland tissue
what is the pathogenesis of sjogren syndrome?
b and t cell mediated inflammatory reaction to target tissues with inflammatory damage followed by fibrotic destruction
what is the clinical presentation of sjogren syndrome?
dry irritated eyes, dry mouth (xerostomia), and difficulty swallowing
how can you make the diagnosis of sjogren syndrome?
if anti-Ro/ss-a or anti-La/ss-B is present; or you can take a biopsy of the lip to look for inflammation of minor salivary gland tissue
what are the complications associated with sjogren syndrome?
extraglandular disease: pulmonary fibrosis; or the lymphoid proliferation becoming clonal leading to lymphoma
what test is used to evaluate dry eyes?
Schiermer’s test
what can dry mouth lead to?
root caries and papillary atrophy (smooth tongue)
what is systemic sclerosis?
fibrosis throughout the body; there is dense collagenous deposition consistent with subcutaneous fibrosis; you will seen vascular hyalinization (vascular changes)
how does systemic sclerosis manifest? (7)
sclerodactyly: the hands get this contracted appearance and the skin has become thick and keratotic; you can also see features of Raynaud phenomenon; reflex, esophageal ulceration; renal crisis; pulmonary hypertension, or pulmonary fibrosis
if you think someone has systemic sclerosis and you do the ANA IF test and it shows a centromeric pattern, what do they most likely have?
CREST syndrome
what is CREST syndrome?
it is like systemic sclerosis but unique; it has a better prognosis than diffuse sclerosis
what are the symptoms/manifestations of CREST syndrome?
C: calcinosis R: Raynaud’s phenomenon; E: esophageal dysfunction; S: sclerodactyly; T: telangiesctasis
what is telangiectasias?
dilation of capillaries causing red marks on the surface of the skin
how might a patient present with complaints of calcinosis?
hard skin nodules, calcium deposits, feels like marbles under skin
what do patients with CREST syndrome have a high titer of?
anti-ribonucleoprotein (RNP)
what is IgG4 related disease?
a constellation of disorders characterized by tissue infiltrates dominated by IgG4 antibody producing plasma cells and fibrosis
what diseases are tied together in one disease known as IgG4 related disease?
autoimmune pancreatitis, riedel thyroiditis, mikulicz’s syndrome, idiopathic retroperitoneal fibrosis
what could be seen of the bile duct in an IgG4 related disease?
the bile duct with sclerosing cholangitis
what is involved in the direct pathway of allorecognition?
an APC from the donor presents the antigen to the host’s T cell; no humeral response involved in the direct pathway
What is involved in the indirect pathway of allorecognition?
an APC of the recipient goes into the graft and pulls out the antigens from the graft and shows them to the recipient’s T cells
which pathway in allorecognition involves both T cell responses and humeral response?
the indirect pathway
Which types of rejection are cell-mediated?
acute cellular rejection and chronic cellular rejection
which types of rejection are humoral?
hyperacute rejection, acute antibody-mediated rejection, chronic antibody-mediated rejection
What is hyperacute rejection mediated by?
pre-formed antibodies
what is hyperacute rejection marked inflammation followed by?
thrombotic microvasculopathy
why would a recipient receive a graft for the first time and already have antibodies against it?
blood group antigens- we are constantly exposed to blood group antigens through bacteria
what is chronic cellular rejection attacking?
the arteries and it creates arteriosclerosis
what is specific to chronic rejection?
fibrosing/ sclerosing process
How do we tell the difference between the antibody-mediated type of rejection and other forms pf cellular rejection?
a C4d stain
What are transplant patients who are on immunosuppressive medications at risk for?
infections; viral: polymavirus and cytomegalovirus; fungal infections, and bacteria infections; also at risk for tumors
What tumors are transplant patients who are on immunosuppressive medications at risk for?
viral induced tumors: lymphomas, Kaposi sarcomas; squamous carcinomas
What occurs during a graft versus host disease?
T-lymphocyte mediated attack on host after transplantation
what are common transplants that have graft versus host reactions?
bone marrow, thymus, and liver
What are the manifestations of graft versus host disease?
skin: rash–> desquamation; liver: jaundice–> cholestasis; intestines: bloody diarrhea–> strictures
What is leukocyte adhesion deficiency type 1?
defective integrins that help it anchor
what is leukocyte adhesion deficiency type 2?
lack of selectin ligand so it can’t initially stop in the circulation
what causes LAD type 2?
there is no fucosyl transferase
what is the inheritance pattern of chediak higashi syndrome?
autosomal recessive
what occurs during Chediak higashi syndrome?
there is failure of phagolysosomal fusion
What are some of the clinical presentations of Chediak higashi syndrome?
easy bleeding/ bruising from platelet dysfunction, grey hair, albinism
What is chronic granulomatous disease?
group of genetic disorders; any genetic disorder that affects the effective killing by ROS; the killing is so inadequate that the body is launching a plan B, which is to basically wall off the infection with granulomas
What do LAD, Chediak-Higashi syndrome, and Chronic granulomatous disease all have in common?
they all share recurrent bacterial infections
what type of infections are LAD, CGD, and Chediak higashi susceptible to?
catalase negative bacteria: streptococcus, enterococcus, staphylococcus aureus
Without the MAC complex, what are patients more susceptible to?
Neisseria meningitis
what happens if you don’t have C1-INH?
unregulated Kallikrein and complement pathways result in severe kinin (bradykinin-) mediated edema; hereditary angioedema
what is the inheritance pattern of hereditary angioedema?
autosomal dominant
What is the inheritance pattern of SCID?
x-linked
What is ADA deficiency?
adenosine deaminase deficiency; accumulation of toxic purine metabolites
What is the effect of ADA deficiency?
it blocks T lymphocyte formation, some B cell influence but lack of helper T cells suppress humoral immune function
What are the disorders of leukocyte function?
leukocyte adhesion deficiency, Chediak Higashi, Chronic granulomatous disease
what are the disorders of complement function?
Membrane attack complex deficiency and hereditary angioedema
what are the disorders of lymphocyte maturation?
SCID syndrome, X-linked agammaglobulinemia, DiGeorge Syndrome
What are the disorders of lymphocyte function?
Hyper IgM syndrome, common variable immunodeficiency, isolated IgA deficiency, and X-linked immunoproliferative disorders
what are the immunodeficiencies associated with systemic disease?
Wiskott Aldrich syndrome and Ataxia-Telangiectasia
What is the main cause of DiGeorge syndrome?
22q11 deletion
what all can be seen in DiGeorge syndrome?
facial and palatal abnormalities, cardiac abnormalities, tetany due to hypocalcemia, immune deficiency due to thymus aplasia
what is x-linked agammaglobulinemia?
a defect in the bruton tyrosine kinase (BTK) gene on the X chromosome
what is the effect of x-linked agammaglobulinemia?
inability of pre-B cells to mature (light chains cannot be rearranged); risk for infection increases
What is a classic presentation of agammmaglobulinemia?
encapsulated bacteria are not phagocytized; so patients come in with recurrent infections of encapsulated bacteria: streptococcus pneumoniae, Haemophilius influenza type B, streptococcus pyogenes, pseudomonas aeruginosa, staph aureus, and protozoa: giardia
What causes hyper- IgM syndrome?
CD40/CD40L mutations leads to the interference of T cells helping B ells class switch
where is CD40L found?
on T cells
where is CD40 found?
on B cells
How do you treat hyper IgM syndrome?
IVIg or stem cell transplantation
What is unique about Common variable Immunodeficiency?
you actually get increased autoimmunity
What is the effect of IgA deficiency?
less defense against inhaled and ingested pathogens: more sinus and respiratory infections, urinary bladder infections, GI infections
What is a possible first indication of IgA deficiency?
transfusion-related anaphylaxis
Why is anal receptive sexual intercourse a common route of transmission of HIV?
because the mucosal barrier is very thin
what effect would a primary chancre of syphillis have on HIV transmission?
it would have a synergistic effect
what is the most common form of parenteral transfer of HIV?
IV drugs
what region of HIV initiates transcription and binds transcription factors?
LTR
what region of HIV encodes for the proteins inside of the virus?
gag
what region of HIV encodes for the surface glycoproteins?
env
what region of HIV encodes for the viral enzymes?
pol
how does HIV bind to a CD4 T cell?
gp 120 binding
how does HIV drill down into the CD 4 T cell?
gp 41
