Immunodeficiencies

Immunodeficiency

The failure of one or more components of the immune system to protect against disease-causing agents

Primary

Immunodeficiency that is present at birth

Secondary (acquired)

immunodeficiency that can be from a variety of causes

- Usually from injury or infection

Primary Immunodeficiency

- Can vary in severity from mild to nearly fatal

- Can be loosely categorized as affecting innate or adaptive responses

t cell deficiency

The likely defect of the opportunistic infection, pneumocytosis, is...

b cell

The likely defect of the opportunistic infection, recurrent bacterial infections, is...

The likely defect of the opportunistic infection, Neisseria (meningococcal disease), is...

opportunistic infections

can be used as clues to spot immunodeficiencies

Patient B

Two patients:

- Patient A: recurrent bacterial infections

- Patient B: recurrent viral + fungal infections

Which patient is more likely to have a T cell defect?

Primary Immunodeficiency (IEI (inborn errors of immunity))

• Due to genetic or developmental defects

- Defects in signal transduction or in cellular communication are common

• Consequences depend on the severity of disruption and specific component involved

• Nature of immune defect determines which pathogens are most dangerous

Combined immunodeficiencies

Primary immunodeficiency that disrupts adaptive immunity (e.g., SCID, BLS)

B-cell immunodeficiencies

Primary immunodeficiency - Depressed production of one or more antibody isotype

Disruption of innate components

Primary immunodeficiency - May also impact adaptive responses (e.g., CAM disruption

Complement deficiencies

Primary immunodeficiency - relatively common; occur in the various steps / pathways

Disruption in immune regulation

Primary immunodeficiency - Can manifest as autoimmunity (e.g., mutation in AIRE gene)

SCID (severe combined immunodeficiency)

Characteristics include:

- Very low number of circulating lymphocytes

- Failure to mount T cell mediated responses

- Thymus does not develop

SCID causes

- IL2RG (common gamma chain (γc), shared by multiple cytokine receptors)

- JAK3 (transmits signals from cytokine receptors that use IL2RG)

- ADA deficiency (breaks down toxic metabolites)

- RAG1/2 mutations (perform V(D)J recombinations in TCRs and BCRs

combined

SCID is an example of ___________ primary immunodeficiency

IL2RG

common gamma chain (γc), shared by multiple cytokine receptors

- common cause of SCID

JAK3

transmits signals from cytokine receptors that use IL2RG

- common cause of SCID

ADA deficiency

breaks down toxic metabolites

- common cause of SCID

RAG1/2 mutations

perform V(D)J recombinations in TCRs and BCRs

- common cause of SCID

SCID

• Results in severe, recurrent infections

• Usually fatal in the early years of life

- Newborn screening and early detection → dramatically improved survival

• Infants suffer from:

- Chronic diarrhea

- Pneumonia

- Skin, mouth and throat lesions

- Various opportunistic infection

T and B cell

In SCID, patients often suffer from infections caused by BOTH viruses and bacteria because both _________________ functions are disrupted

SCID Treatment

- Bone marrow transplants (Hematopoietic stem cell transplant)

- Gene therapy to repair leukocytes

Immunodeficiency Treatment

Generally treated via replacement therapy

- Replacement of a missing protein

• Passive Ig, recombinant proteins

- Replacement of a missing cell type or lineage

• Bone marrow or Hematopoietic Stem Cell transplantation

- Replacement of a missing or defective gene

• Gene therapy

Gene Therapy

Earlier ________________ trials had safety concerns, but newer approaches have improved safety and are now clinically used in some immunodeficiencies (e.g., ADA-SCID)

secondary

AIDS is an example of _____________ immunodeficiency

HIV

affects all populations

• Transmission risk behaviors:

> Unprotected sex

> Needle sharing

> Vertical transmission (now largely preventable)

HIV

is now a chronic manageable disease

Major issues:

• Access to care

• Global disparities

• Stigma

HIV-1

Two RNA genomes + reverse transcriptase (RT) enzyme

2 RNA genomes + RT enzyme (reverse transcriptase)

HIV-1 consists of...

HIV-1 Infection

• Most common means of transmission

- Vaginal/anal intercourse

- Receipt of infected blood/blood products

- Passage of HIV from mother to infants

T cells

HIV-1 is not limited to _________

- Dendritic cells in virus-exposed areas may take up and harbor virus, passing it to CD4+ T cells

Infection of Target (HIV Replication)

1. HIV binds receptors on target cell

2. Fusion with target cell membrane

3. Nucleocapsid containing viral genome and enzymes enter cell

4. Viral genome and enzymes are released

5. Viral reverse transcriptase catalyzes reverse transcription of ssRNA, forming RNA-cDNA hybrids

6. Original RNA template is partially degraded, followed by synthesis of second DNA strand to yield dsDNA

7. The viral dsDNA is translocated to the nucleus and integrated into the host chromosomal DNA by the viral integrase enzyme

Activation of Provirus (HIV replication)

1. Transcription factors stimulate transcription of proviral DNA into genomic ssRNA and, after processing, several mRNAs

2. Viral RNA is exported to cytoplasm

3. Host-cell ribosomes catalyze synthesis of viral precursor proteins which are then cleaved by viral protease into viral proteins

4. HIV ssRNA and proteins assemble beneath the host-cell membrane

5. The membrane buds out, forming the viral envelope, released viral particles complete maturation

Nucleocapsid

After HIV binds receptor on target, and fuses with cell membrane, __________________ containing viral genome and enzymes enter cell and are then released

- part of HIV Replication (Infection of Target)

RNA-cDNA hybrids

Once viral genome of HIV is released, viral reverse transcriptase catalyzes reverse transcription of ssRNA, forming...

- part of HIV Replication (Infection of Target)

dsDNA

after formation of RNA-cDNA hybrids, original RNA template is partially degraded, followed by synthesis of second DNA strand to yield...

- part of HIV Replication (Infection of Target)

nucleus

The viral dsDNA of HIV is translocated to the _________ and integrated into the host chromosomal DNA by the viral

- part of HIV Replication (Infection of Target)

cytoplasm

Transcription factors stimulate transcription of proviral DNA into genomic ssRNA and, after processing, several mRNAs.

- next, Viral RNA is exported to ___________

- part of HIV Replication (Activation of Provirus)

Host-cell ribosomes

once viral RNA is transported to the cytoplasm ________________________ catalyze synthesis of viral precursor proteins which are then cleaved by viral protease into viral proteins

- part of HIV Replication (Activation of Provirus)

viral envelope

HIV ssRNA and proteins assemble beneath the host-cell membrane then the membrane buds out, forming the _____________, released viral particles complete maturation

- part of HIV Replication (Activation of Provirus)

CD4+ T cells

HIV-1 Infection causes Depletion of _____________

- Blood

• Reaches steady state

- Lymph nodes and GI tract

• Destruction continues during chronic stage

• Infection of lymph via dendritic cells

• Swollen lymph nodes, fever and sometimes rashes

• Infection usually goes unnoticed until opportunistic infections begin to occur

Th cell coordination of immune responses

HIV primarily infects CD4⁺ T cells. Which immune function is MOST directly impaired early in infection?

acute, asymptomatic, AIDS

HIV-1 infection causes gradual loss of immune function in 3 phases; these phases are...

Acute Phase (HIV Infection)

• Spike in HIV levels in blood

• Eventually brought mostly under control by production of anti-HIV antibody

Asymptomatic phase (HIV infection)

• Lengthy, possibly years

• Gradual decrease in CD4+ T cells and increase in viral load

AIDS (HIV infection)

• Crash in CD4+ T cell numbers

• High levels of HIV in blood

opportunistic infection

Untreated AIDS can lead to death from _______________________

- Yeast infections (usually first sign)

- Fungal infections (pneumonia)

- Cancer (cervical, lymphoma, viral induced)

- Parasitic infections (severe wasting diarrhea)

- Frequent viral infections (HSV, pneumonia)

- Bacterial infections (Tuberculosis, pneumonia)

CD4+ T Cell

Opportunistic infections typically appear late in HIV infection rather than immediately after infection because the immune system usually compensates despite _______________ loss

Anti-retroviral Drugs

Treatment of HIV/AIDS is __________________

- Lowering of viral load and relief from infection

- Target aspects of the viral replication cycle

- Prevent virus from fusing with and entering a cell

- Interfere with reverse transcription

- Block viral protease needed for construction of new virions

*Must be careful not to accidently target normal cell processes

HIV replication

Antiretroviral therapy inhibits ________________________.

Target steps in the HIV life cycle:

● chemokine receptor antagonists

● fusion inhibition

● RT inhibition

● integrase inhibition

● protease inhibitors

integration of viral DNA into host genome

A drug blocks HIV integrase. What step in the viral life cycle is directly inhibited?

Antiretroviral Therapy (ART)

• High mutation rates make individual drugs less useful

• Combination of drugs with different mechanisms

- Unlikely that mutations can side step ALL drugs involved

• Very effective; can reduce viral loads below limits of detection

- U=U (Undetectable = Untransmittable)

- Near-normal life expectancy with treatment

• Can be used prophylactically in high-risk groups (e.g., PrEP)

HIV-1 Vaccine

• Difficulties

- Most vaccines allow low level infection

- HIV has a rapid mutation rate

- Killed HIV does not retain antigenicity

- There is no suitable animal model for testing

- Until recently had no known natural immunity to mimic

• Still no widely available vaccine, BUT:

- mRNA and broadly neutralizing antibody (bNAb) research is ongoing

- Some recent trials showed partial efficacy

Complement

The likely defect of the opportunistic infection, Neisseria (meningococcal disease), is...