PATH 201 - LECTURE 20

What are the 2 main types of immune deficiencies

• primary congential

• secondary acquired

what are the types of primary immune deficiencies

• innate

• adaptive

what deficiencies or defects are innate immunity deficiencies

• defects in:

• TLR signalling

• complement

• leukocytes adhesion

• phagolysosome function

• microbicidal activity

describe the scope of conditions that come about from mutations in toll like receptors

very specific because toll like receptors are specific

give an example of a defect in TLR and the innate defiency it causes

• mutation in TLR3 gene develop herpes simpex encephalitis because TLR3 recognises dsDNA which is the basis for herpes simplex

what are the types of leukocyte adhesion deficiencies

• LAD 1 and 2

describe the conseqeunce of leukocyte adhesion deficiencies

• impaired leukocyte adhesion, therefore phagocytic cells cannot migrate through the tissue and phagocytose anything

describe survival against LAD 1

fatal within 1 year

what are the 3 main parts of complement that are affected by innate deficiency

• classical pathway

• c3

• lysis pathway

describe what deficency in the classical pathway leads to

• classical helps clear immune complexes that have been opsonised with antibody

• therefore deficiency in this leads to inability to clear this and we get diseases related to immune complexes like SLE

describe what deficiency in the c3 pathway leads to

• c3 is related to effective opsonisation

• without it we get impaired phagocytosis and recurrent pyogenic/bacterial infections

describe what deficiency in the terminal components (c5-c9) leads to

• these are invovled in the membrane attack complex

• Deficiency → recurrent Neisseria infections, because direct complement-mediated killing is especially important for defence against these bacteria.

what does defect in microbicidal activity lead to

• chronic granulomatous disease

describe how microbicidal activity leads to chronic granulomatous disease

• genetic deficiency in ROS

• killing doesnt occur

• instead micrboes are surrounded by activated macrophages causing granulomas

• result is recurrent life threatening bacterial and viral infections

what does defect in phagolysosme formation lead ot

• cheidak higashi syndrome

explain cheidak higashi syndrome

• Microbe engulfed → defective phagolysosomal processing → impaired destruction.

  Cytotoxic granule release is also affected.

• susceptibility to bacterial and fungal and viral infection

• most dont live past teens

what is the main antigen presenting cell

dendritic

what do cd4 t cells do

• secrete cytokines

what do cd8 t cells do

• secrete cytokines

• induce apoptosis

what MHC do cd4 t cells respond to

MHC I

what MHC do CD8 T cells respond to

MHC II

what is the overall fucntions of the cytokines that CD4 release

• inflammation

• activation of macrophages

• T and B cell activation

what are the subsets of CD4 helper cells

Th1

Th2

Th17

what does Th1 do

• macrophage activation

• stimulatuon of IgG antibody production

what cytokine activates Th1

• IL 12

• IFN Y

what does Th1 release

IFN Y

what cytokines does Th2 release

• IL4

• IL5

• IL13w

what does Th2 do

• stimulates IgE

• activates mast cells and eosinophils

what cytokine activates Th2

IL 4

what does Th17 do

• recruits neutrophils and monocytes

what does Th17 release

• IL17

• IL22

• chemokines

what is Th17 activated by

• TGF b

• IL1

• IL6

• IL23

describe the effects of B cell deficinecy

inadequate antibody production.

That means:

• Less antibody-mediated opsonisation.

• Less toxin neutralisation.

• Poorer antibody responses to vaccination.

what is the effect of B cell deficiency on delayed hypersensitivity response and graft rejection

• no effect becaysee mainly involves T cells

what are the effects of T cell defiecinecy

• The person has difficulty controlling:

  • Viruses.

  • Fungi.

  • Intracellular bacteria.

  • Other opportunistic pathogens

describe effect of T cell deficinecy on delayed hypersensitivity

• DTH, is a T-cell-mediated inflammatory response, such as the response assessed by a tuberculin skin test. It becomes weak when the relevant T-cell function is deficient.

describe effect of T cell deficinecy on graft survivial

• increased because T-cell-mediated rejection is impaired.

example of B cell defiicnecy

X linked agamma globulinemia

what is X linked agamma globulinemia

a defect in Bruton tyrosine kinase, BTK, blocks development around the pre-B-cell stage.

what is the consequences of x linked agamma globulinemia

• Mature B cells are markedly reduced.

• Plasma cells are markedly reduced.

• Antibody levels are very low OR ineffective

• T-cell responses are relatively preserved.

• leads to recurrent infections

who does brutons disease affect

• males bc its x linked

• asymptomatic in females

what is an example of a T cell deficinecy disease

DiGeorge syndrome

what is digeorge syndrome

abnormal thymic development which leads to incomplete T cell maturation

what is the consequences of digeorge syndrome

• no T cell mediated response

• no class switching of antibodies - just IgM

• high susceptibility to infection

what is a severe combined immunodeficinecy

when the precursor to B and T cells are affected and so theyre both affected

what is an example of a SCID

• ADA deficinecy

what is ADA

adenosine deaminase is an enzyme that is involved in purine metabolism

what does lack of ADA cause

• accumulation of metabolites that are toxic to lymphocytes

describe the consequnece of ada deficincy

Both major adaptive defence systems are compromised, leaving susceptibility to a broad range of pathogens.

how is ADA treated

• bone marrow transplant: healthy blood-forming stem cells can supply functional immune-cell precursors

• gene-therapy: correcting the defect in the patient’s own stem cells.

what is secondary immune deficinecy

• it is acquired

when do we see secondary immune deficiency

• malnutrition

• cancer

• chemotherapy

• infections

• autoimmune diseases

how can someone with measles have secondary immune deficiency

• measles is causing a strong Th1 response

• this pushes Th1-Th2 balance to a Th1 predominance which means we are more susceptible to conditions that relate to Th2 and Th17

how can someone with a cancer/neoplasms have secondary immune deficienct

cancer affecting lymphocytes or myeloid cells can cause overproduction of a specific cell type in our blood which means are cells effectively get crowded out

how can chemo cause secondary immune deficiency

can cause neutropenia

how can malnutrition cause secondary immune deficinecy

Limits resources needed to maintain barriers, immune cells and responses

what is HIV

• virus that can cause secondary immune deficinect

describe how HIV infects

• envelope protein gp120 binds CD4

• CD4 on CD4 T cells, macrophages and dendritic cells

• After entry, reverse transcriptase produces viral DNA from the RNA genome, and viral DNA can integrate into the host genome.

how does HIV cause reduction in CD4 numbers

• cells that the virus replicate within dies

• HIV persists, so the immune system keeps receiving stimulation. T cells become chronically or repeatedly activated, which can trigger pathways that make them undergo apoptosis.

• infected CD4 cells by HIV-specific CD8 cytotoxic T cells - so here we are trying to kill the infected cells but we are also killing of CCD4 t cells bc those are the infected cells

what are some HIV associated opportunistic infections

• opportunistic infection causing pneumonia

• recurrent mucosal candidiasis

• severe herpes simplex

• disseminated mycobacteria Tb that spreads past lungs

• toxoplasmosis of the nervous system