Immuno: Immunodeficency

infections due to autoimmunity

• t cell

  • viral, protozoan, fungi

• b cell

  • bacterial infection

• B and T cell

  • combined immunodeficiency

• phagocytic cells

  • common bacterial infections, lack pus

• complement

  • bacterial infection, autoimmunity

warning signs

• multiple infections within a year

• 1+ months of antibiotics and no affect

• fail to gain weight

• frequent skin abcess

• family history

SCID

• group of diseases

• virutaly any infection

• x linked SCID 50%

  • mutation in the y chain of IL-2R

  • IL-4, 7, 9, 15

• autosomal recessive SCID

  • mutation in JAK3 kinase

  • transmit signal from the T1 receptor

• JAK STAT = no signal or the body doesn’t transduce the signal

• any step can go wrong when developing myeloid or lymphoid cells from hemapoetic stem cells

More SCID

• recombinase deficiency

  • RAG genes

• adenosine deaminase deficiency

  • purine salvage pathway

  • lymphocyte sensitivity

  • 1st successful gene therapy

• bare lymphocyte syndrome

  • MHC II gene transcription factor

  • low CD4+ (no T helper cells)

  • Th cells are functional if they artificially stimulated

T cell deficiency

• digeorge syndrome

  • developmental defect lack of T cells

  • lack thymus and parathyroids

  • B cells are normal

  • treatment fetal thymic transplant

• chronic mucotaneous candidias

  • repeated candida albicans (fungi)

  • continval yeast Tc defect manage fungal

B cell disorder

• bad ab production

• x linked agammaglobulinemia

  • mutation in the tyrosine kinase - signal transduction

  • no Ig

  • bacterial infections

• transient hypogammaglobulinemia

  • premature birth

  • dont make enough ab

  • hypothermia or starvation

• common variable ID

  • fail of Ig secretion

  • low IgG + IgA + normal IgM

  • repeated bacterial infection, autoimmunity

• selective Ig deficiencies

  • IgA

  • cause is unknown

B and T interaction disorders

• hyper IgM syndrome

  • X linked

  • low IgG, A, E failure to class switch

  • mutation in CD40 ligand

• x linked lymphoproliferative lymphoma

  • EBV infections constant and severe

  • fail T cell regulation of B cell (stop listening to signals)

  • cause is unknown

phagocyte dysfunction

• leukocyte adhesion deficency

  • LAD I

    • integrin beta subunit

    • common LFA, MAC1

    • bacterial infections causes tissue infection

    • increase in WBC count without pus

  • LAD II

    • selectin ligand

• chronic granuomatous disease

  • defect in toxic O2 product production in phagolysosome

    • neutrophils and phagocytes dont digest

  • repeated bacterial infections, skin infections

  • Increase in lymph node size. due to inflammation

  • easier to manage with ab

Complement deficiency

• early components (C1,2,3,4)

  • bacteria infect (capsule)

  • immune complex disease

• late compounds (C5-9)

  • MAC deficency

  • G- bacteria infects

• control defect

  • C1 esterase inhibitor

  • edema

treatment

• none are great

• ab

• IVGG

  • normal human serum with Ig against common pathogens need blood donations for this

• enzyme replacement

  • inject C1 esterase inhibitor

• cell replacement

  • HLA matched stem cells

• gene transfer

  • gene regulation is important

• bone marrow transplant

  • donors are hard to get, it is also hard to match.

AIDS

• there are many people living with HIV

• there has been a great drop in death, used to be the leading cause of death

• stigma against homosexual males

• 1st case in NYC 80s

• pnemocystis carni pnemoniae

  • started in elderly men then started showing up in young males

• kaposi sarcoma (virally induced skin cancer in men)

• loss of CD4+ T cells and cell mediated immune function

• when there are new diseases people become marginalized

AIDS/HIV Effect on life expectancy

• early 1900s death due to infant mortality

• peak - almost all due to HIV

• hard to get people to fund

HIV

• retrovirus

  • RNA genome, has reverse transcriptase

  • provirus inserted into host genome

  • rare converts RNA genome to DNA inserts into the host chromosome

• HIV-1 = most common virulent strain

• HIV-2 = africa, less virulent

• related to HTLV-1 SIV

• structure

  • envelope

  • matrix

  • capsid

  • RNA

  • associated enzymes

  • GP120 binds to CD4+ Th affected

envelope

• lipid bilayer from host

  • virus buds off - goes to infect other cells

  • contains host molecules MHC

• virally encoded membrane glycoprotein

• GP41

  • transmembrane proteins - required for fusion

• GP120

  • associated with GP41

  • bind CD4

• virus speed

• tight

  • infected HIV (T cells)

  • green dots are the virions

  • can bud odd T cell already contact with another cell

• attach

• fuse membrane

• coat with ab

• make DNA genome

• LTR integrated to another cell

• becomes part of the genome over time

Transmission

• most likely through transfer of infected cells

  • fluid - blood, milk, semen, saliva

  • vertical - through birth

• sex - blood - risk

• risk hierarchy

  • IV drug use

  • anal intercourse

  • vaginal intercourse

  • oral sex

  • no through misquotes

Sex workers

• started to see on dendritic cells and macrophages

  • look at sex workers

  • did not get HIV even though they were exposed many times

  • they had a mutation of the CCR5 gene so no macrophages could be infected

  • less susceptible to virus

• takes weeks to recover

• slow and steady decline of CD4

• infectious for yrs after the immune system stops working

Diagnosis

• anti HIV ab

  • check for circulating ab

  • ELISA and western blot

  • 2-6 months

• viral RNA

  • PCR

• CD4 count

  • less than 200

• indicator for diseases

  • pneuemocysistis carninii

  • kasposi sarcoma

  • canidia albicans

  • unusual mycobacteria

anti HIV western

• ELISA

  • turns orange then we know there is circulating ab

  • antiserum from patient stuck

  • can be cross reactive

  • if you get a positive ELISA then you need to do a western blot

  • transfer the protein to a membrane to detect ab

  • seperate the proteins by molecular weight

  • if all the bands match we know the patient had been infected

clinical course

• acute

  • flu like symptoms, fever, sweats, cough

  • CD4 decreases

• latent

  • 6 months - 15 years

  • slow replication of CD4 gradually decreasing

  • CD4:CD8 2:1 reverses

• crisis phase

  • opportunistic pathogen/infection

  • unusual malignancy

  • CNS effects

Treatment

• prevent

  • blood screening

  • needle exchange programs

  • condoms

  • treat the infected mother

• chemo

  • repurposed chemotherapy durgs

  • reverse transcriptase

• protease

  • norvir

  • has less side effects

• integrase

• attachement

anti retroviral therapy

• HIV increases and mutates to become drug resistent

• HAART

  • rotate drugs to target different parts of the life cycle

• prep

  • pre exposure prophylaxis

  • use if you know you will be exposed soon

• PEP

  • psot exposure

  • accident needle pokes, birth, etc.

• there has been a small improvement in people with this disease it has become manageable

• this is most common in less affluent countries hard to get treatment because it is expensive

• kids born with the disease have decreased

• usually affect 30-40 yr olds take care of young and old

• ab against it but it is not protective you need active ab

• mimic immunity

• no vaccine currently