Disorders of the Immune System

autoimmune diseases

cause by activation of self-reactive helper T-cells due to lack of self tolerance; types: cell mediated and Ab-mediated (most common)

hypersensitivity

autoimmune reactions such as lupus, Grave's, myasthenia gravis, RA, MS

development

factors that influence autoimmune disease _________________________:

-genetics (HLA)

-hormonal factors (90% occurs in women, probably due to estrogen)

-environmental: bacteria or viruses, drugs, or heavy metals

multiple sclerosis

autoimmune disorder in which autoreactive T-cells and activated macrophages cause demyelination of the white matter of the brain

insulin-dependent diabetes melitus

autoimmune disorder in which autoreactive T-cells destroy the islets of pancreas

guillain-barre syndrome

autoimmune disorder that is the most common cause of acute paralysis in the US; produces antibodies against myelin

crohn's disease and ulcerative colitis (IBD)

autoimmune disorder in which there is chronic inflammation of the ileum caused by abnormal immune response to normal GI flora

Rheumatoid arthritis

autoimmune disorder in which autoantibodies against IgG called rheumatoid factor

rheumatic fever

autoimmune disorder in which antibodies against the M protein of group A strep which cross reacts with myosin of the heart

congenital

immunodeficiency disorders that are innate; rare and poorly understood genetic disorders

-thymic dysplasia

-X-linked hypogammaglobulinemia

-primary T and B-cell deficiencies

-complement deficiency

-phagocytic dysfunction

secondary

immunodeficiency disorders due to acquired disease:

-HIV/AIDS (CD4)

-malignancy - Hodgkin's Lymphoma, bone marrow

-irradiation

-immunosuppression drugs

-liver disease, diabetes

B-cell deficiencies

symptoms: recurrent infections with pyogenic bacteria (staph) - otitis media, pneumonia

ex: hypogammaglobulinemia - very low levels of Igs and absence of B-cells

IgA deficiency - recurrent sinus and lung infections

T cell deficiencies

symptoms: recurrent infections with fungi, viruses, protozoa

ex: thymic aplasia (DiGeorge's syndrome) - thymus fails to develop properly

Combined B and T cell deficiencies

symptoms: recurrent infections caused by bacteria, viruses, functi, and protozoa occur in infancy

ex: SCID - T and B cells are absent or very low numbers, hereditary

phagocyte deficiencies

cell deficiency: severe infections (bacterial and fungal) are common

complement deficiency: susceptibility to a variety of infections to increase in autoimmune disease incidence

codominant

A and B genes that encode for specific sugars on surface of RBCs are _______________

transfusion

___________________ reaction due to antigen-antibody reaction is a type II-cytotoxic hypersensitivity reaction

O

universal donor blood type; has anti-A and anti-B antibodies

AB

universal recipient blood type - does not have antibodies against A or B

A

blood type with A antigen and anti-B antibody

B

blood type with B antigen and anti-A antibody

erythroblastosis fetalis

result of passage of maternal IgG anti-Rh antibodies through the placenta to the fetus, causing lysis of fetal erythroblasts

Rho-Gam

high titer Rh immune globulins given to mother at 28 weeks of gestion and upon delivery; prevent Rh+ erythrocytes form acting as sensitizing antigen so erythroblastosis fetalis does not occur

+, -, second, +

erythroblastosis fetalis is only a concern if the father is Rh______, the mother is Rh_______, and the ___________ child is Rh_______

first

even if the father is Rh+, the mother is Rh-, and the ___________ child is Rh+, there is no risk for erythroblastosis fetalis

MHC I

glycoproteins responsible for recognition of self and non-self; found on the surface of virtually all nucleated cells

MHC II

glycoproteins recognized by T helper cells that will activate cytotoxic T cells to attack donor tissue

HLA (human MHC)

human leukocyte antigens; alloantigens; genes are clustered in the MHC

autologous graft

graft in which donor and recipient are the same person; don't require any immunosuppression because the graft is coming from the person's own tissue

syngeneic graft

graft in which the donor and recipient are identical twins

allogenic graft (allograft)

graft in which the donor and recipient share similar HLA types and same blood type (most common)

xenograft

graft in which the donor and recipient are different species (ex: pig --> human)

CD8 T cells

play the most important role in transplant rejection; reactions cause killing of allograft cells when foreign MHC activates immune response

necrosis

develops from transplant rejection of untreated

HLA

better _________ match between donor and recipient = longer graft survival

GVH (graft versus host disease)

occurs when a graft contains immunocompetent T-cells from the donor, the host is immunocompromised, and the host expresses antigens foreign to the donor causing the donor T cells to attack the host

T cells

to prevent GVH, treat donor tissue prior to transplant to eliminate mature __________ from the graft that will attack recipient tissue

calcineurin inhibitors

Cyclosporine (Neoral, Sandimmune, Gengraf)

Tacrolimus (FK506, Prograf)

mTOR inhibitors

Sirolimus (Rapamycin, Rapamune)

antiproliferative agents

Azathioprine (Imuran)

Mycophenolate mofetil (Cellcept)

corticosteroids

prednisone (Deltasone)

T lymphocytes

rejected graft tissue is highly infiltrated by ______________________

calcineurin inhibitors (cyclosporine and tacrolimus)

Inhibit calcineurin-dependent dephosphorylation: results in no IL-2 transcription which means no proliferation of T cells

tacrolimus (Prograf)

macrolide lactone antibiotic; decreases expression of IL-2 and therefore decreases T-cell proliferation; approximately 100-fold more potent than cyclosporine and 10-fold more potent inhibiting T cell activator

Used to prevent and treat acute rejection

prevent, treat

Cyclosporine and Tacrolimus can both be used for _________________, but only Tacrolimus is potent enough to _____________ acute rejection

Sirolimus (Rapamycin, Rapamune)

macrolide antibiotic; acts specifically by binding the TOR protein kinases which prevents cell cycle progression by blocking the ability of T cells to proliferate in response to IL-2 stimulus; used in prevention of acute rejection

pharmacologically different from both CsA and Tacrolimus

cannot

Cyclosporine and Tacrolimus __________ be mixed because the have the same mechanism of action, but they can be taken at the same time as Sirolimus

synergistic

sirolimus is _____________ with calcineurin inhibitor: in combination with cyclosporine and steroids

Mycophenolate mofetil (CellCept)

semisynthetic derivative of mycophenolic acid from fungus; inhibit de novo purine synthesis by inhibiting the enzyme inosine monophosphate dehydrogenase (IMP) that is crucial for purine synthesis

reduces or stops T and B lymphocytes proliferation by blocking the formation of GMP - prevents nucleic acid synthesis

IMP dehydrogenase

mycophenolate mofetil (CellCept) inhibits ______________________________, preventing the proliferation of B and T cells (blocks purine synthesis)

6-mercaptopurine (Purinethol) and azathioprine (Imuran)

reduce or stop T and B cell proliferation by interfering with purines on DNA or RNA

steroids

used for almost all transplant patients (paired with other drugs); very safe and specific to T-cells; lipophilic drug targets nuclear receptors (transcription mechanism of action); causes T-cells to undergo apoptosis

tumor

____________-specific T-lymphocytes and antibodies detected in patients with cancer; able to evade immune response by secreting immunosuppressive cytokines and downregulate MHC-I

inhibiting

cancer drugs work by ___________________ the hiding of tumors from our immune systems

escape

mechanisms of tumor ________:

-engagement of inhibitory molecules (CTLA-4, PD-1)

-secretion of immunosuppressive cytokines

-loss of tumor antigen expression

-downregulation of MHC-I

cancer

cells involved in __________ immunology:

-innate: NK, macrophages, DCs

-adaptive: T cells

vaccination

use of inactivated whole germs (pertussis, influenza, Polio), close relative (tuberculosis-BCG) or component antigens (Tetanus, diphtheria, hep A and B) to develop immunity to pathogens. Goal is to provide long-lasting and protective immunity

1 billion

it is estimated that vaccines have saved more than __________________ lives

herd immunity

the resistance to the spread of a contageous disease within a population that results if a sufficiently high proportion of individuals are immune to the disease, especially through vaccination

attenuated

use of ___________ organisms reduces pathogenicity which can stimulate protective immunity but not cause disease; relies on replication within host cells, generating both T cell and Ig immunities.

immunocompromised

Attenuated vaccines provide excellent immune responses but are dangerous for __________________ patients

inactivated

vaccine that uses killed or purified components of organisms (proteins, mRNA, adenovirus) that would be as effective as live whole organisms

desirable because it is safe for immunocompromised patients and is stable upon storage

adjuvant

enhances immunogenicity of vaccines; not specific to any particular disease but is added to all vaccines

years

vaccines give sustained protection that lasts against illnesses for several ___________

neutralizing

vaccines induce __________ antibody; prevents infection of non-replaceable cells such as neurons

cell mediated

some pathogens, particularly intracellular, are more effectively dealt with by ______________ responses (vaccines induce protective T cells)

practical

low cost per dose, biological stability, ease of administration, and few side effects are ___________ considerations for an effective vaccine

point of entry

the ideal vaccination induces host defense at the __________________________ of the infectious agent

oral

route of vaccine administration with the goal of stimulation of mucosal immunity for organisms that enter mucosal surfaces

injection

most vaccines are given by _____________ which are painful, have reduced vaccine uptake, expensive, laborious, and do not mimic the usual route of entry

murine

antibody that is 100% mouse; foreign to humans and will elicit immune response

chimeric

antibody in which the Fc region is entirely human and the Fab region is murine

humanized

antibody that is mostly human but has murine portions of the Fab region that interact with antibody

human

antibody that is 100% human; the only type of antibody therapy that does not require an immunosuppressive drug

mouse

-omab

chimera

-ximab

humanized

-zumab

human

-(m)umab