immunodeficiency and HIV

immune system - refresher

Immune system:

• Innate (ex: phagocytes, complement)

• Adaptive (ex: T cells, B cells)

• Central role to protect against microbial pathogens

Compromised defence if one or more components absent or deficient

Immunodeficiency results in

• increased susceptibility to infection by specific classes or types of microbes

• Repeated or unusual infections is an indication of immunodeficiency

Primary immunodeficiency

• Genetically determined or result of developmental anomalies

• Inherited, congenital, and rare

Secondary immunodeficiency

• Acquired.

• Caused by disease or an immunosuppressive treatment

• More common.

genetic primary immunodeficiencies

• Autosomal or…

• X-linked (sex chromosome)

• Gene deletions rearrangements, polymorphisms (SNPs)

Biochemical or metabolic primary immunodeficiencies 3

1. Adenosine deaminase deficiency (T cells)

2. Purine nucleoside phosphorylase deficiency (T cells)

3. Developmental arrest (B cells, T cells, Phagocytes

complement deficiency - primary immunodeficiency 

complement deficiency - General increased susceptibility to bacterial infections, especially Pneumococcus, Streptococcus and Neisseria

Classical pathway deficiencies (C1qrs, C2 or C4)

Immune complex disease

• unable to remove Ag-Ab complexes (Type III hypersensitivity)

Susceptibility to encapsulated organisms

• Streptococcus pneumoniae and Neisseria spp

C3 deficiency (C3b, CR1 and CR3)

Opsonisation of microbes is defective

• removal by phagocytosis is compromised

• susceptibility to encapsulated organisms i.e. Streptococcus, Neisseria, pyogenic organisms

Alternative pathway deficiencies (Factor B, Factor D and Properdin)

Results in low C3b levels - defective phagocytosis 

• pneumococcal and meningococcal infections

• no immune complex disease - as there is no antibody involvement 

MAC complex deficiency (C5-9)

Inability to lyse bacterial cells

• recurrent infection with Neisseria meningitidis

• humoral (antibody) immunity is unaffected

primary immunodeficiency - phagocytosis deficiencies 

intrinsic deficiencies - deficiencies in the actual cells that perform the phagocytosis functions

General increased susceptibility to bacterial and fungal infections of skin and mucosal tissues

Treatment: antibiotics or bone marrow transplant (gene therapy)

treatment for phagocytosis therapies

antibiotics or bone marrow transplant(gene therapy)

primary immunodeficiency - Stem cell differentiation - 

1. Neutropaenia (low neutrophil numbers)

2. Leukocyte adhesion disease

lack of adhesion molecules (CD18, that binds to ICAM-1 in epithelial cells - oveming of neutrophils) required for Neutrophil recruitment

primary immunodeficiency - phagocytosis (Chediak-Higashi syndrome)

Lack of phagosome fusion with lysosomes

• defect in lysosomal trafficking regulator (LYST) - organism will not be killed

• susceptibility to staphylococcus aureus

primary immunodeficiency - Defective intracellular Killing (Chronic granulomatous Disease)

Defect in NADPH system - required for free radical formation (ROS) → lack of oxygen-dependent killing

• increased bacterial and fungal infections

primary immunodeficiencies - humoral/antibody deficiencies 

Recurrent extracellular bacterial infections (Pneumococcus, Streptococcus, Haemophilus, mainly encapsulated bacteria) Treatment: life-long or periodic gamma globulin injections

humoral/antibody deficiency treatments

Treatment: life-long or periodic gamma globulin injections

primary immunodeficiencies - B cell development - 2 examples 

1. Bruton’s agammaglobulinaemia (xlinked agammaglobulinaemia)

2. Defect in Bruton’s tyrosine Kinase

• Few or no mature B cells / antibody

• Blockage in maturation of pre-B to B cells, while T cell maturation is normal

• Common in male infants; protected for 6-months, then recurrent bacterial infections

humoral/antibody deficiencies → Failure of class switch from igM (hyper igM syndrome)

• Increased igM but little or no IgG - Lack of igG antibody opsonization and phagocytosis (ex, defective CD40 on B cells or CD40L on T cells)

• defects in opsonisation

• both T and B cells can be affected  

humoral/antibody deficiencies - Common variable immunodeficiency (many potential causes but not completely known)

• IgG/IgM/IgA deficiency - either B cells do not undergo terminal differentiation (no IgG/IgA)

• or T cell signalling is defective - adults of box sexes (late onset, 15-35 yrs)

• affects both B and T cells 

T cell deficiencies - primary immunodeficiency 

• Opportunistic infections (viruses, fungi, parasites, bacteria).

• Often fatal in early years of life.

• Treatment: bone marrow transplant (gene therapy)

T cell deficiency - treatment

Treatment: bone marrow transplant (gene therapy)

T cell deficiency - Lack of a developed thymus - DiGeorge’s syndrome

• Lack of T cells - susceptibility to many infections→abnormal B cell immunity as T cells activate B cells 

• hypoparathyroidism (resulting in hypocalcaemia and congenital heart disease)

T cell deficiency -  Stem cell defect or death of developing T cells

Severe combined deficiency syndrome (SCID) - Defect in the common gamma chain used by cytokine receptors (IL2/4/7/9/15/21) in 50% of cases - Adenosine deaminase deficiency or purine nucleoside phosphorylase deficiency in 25% of cases (metabolite build up inhibiting DNA synthesis)

T cell deficiencies - MHC II deficiency

• No mature CD4+ T cells

• Low antigen presenting cell function, reduced B/T cell activation (no antibodies)

• Death by yr 5 due to bacterial and viral infections

Clinical features of Immunodeficiencies 8

1. Chronic and recurrent infections

2. Unusual microbial agents

3. Incomplete responses to treatment

4. Skin lesions, warts

5. Diarrhoea

6. Recurrent abscesses

7. Autoimmunity

8. Failure to thrive

Secondary Immunodeficiencies 6

1. Therapeutic drugs (cancer chemotherapy, radiation therapy, post-transplant immunosuppression)

2. Infection (HIV/AIDS)

3. Metabolic / chronic disorders (ex: diabetes)

4. Malnutrition

5. aging

6. Burns/trauma (loss of immunoglobulin via damaged skin)

HIV pandemic

• 38.4 million people currently living with HIV

• 1.5 million new infections in 2021

• 0.5 million deaths in 2021 

Human Immunodeficiency virus

• Causative AIDS agent

• Baltimore virus classification: Group VI (ssRNA virus with a DNA intermediate)

• Hallmarks: Reverse transcription (RNA -> DNA) and chromosomal integration

• once they merge from cell - envelope delved from plasma membrane - as it matures it will form a core with a characteristic conical shape 

• outer layer/envelope

• core→ protein capsid

• viral genome and viral enzymes

• pro vial DNA that is integrated into the host - long terminal repeats 

• gag - structural proteins 

• pol - viral enzymes - reverse transcriptase and viral integrase → originals are present in the virus to begin with  

• env - envelope 

• rav and tat - regulatory proteins 

• accessory proteins enhance viral infection

Human Immunodeficiency virus life cycle and cell entry 11

1. receptor binding - viral envelope protein interacts with CD4 and co-receptors - CCR5 or CXCR4

2. Fusion of viral membrane with target cell membrane 

3. uncoating and reverse transcription via viral RT enzymes

4. nuclear entry 

5. integration into host chromosomes

6. transcription

7. RNA processing

8. nuclear export

9. translation

10. assemble of progeny

11. budding 

virus only has 9 proteins - many of these steps require host proteins 

Cellular infection by HIV - attachment factors

• Heparan Sulphate Proteoglycans

• Galactosylceramide

• alpha3beta7 integrin

• DC-SIGN

relatively non specific

not essential

Cellular infection by HIV - receptor

CD4 - requires co receptors

Cellular infection by HIV - coreceptors

• CCR5 (macrophages and DCs dendritic cells/langerhans cells) - antiviral that bind to CCR5 can be used in antiretroviral medicine 

• CXCR4 (T cells including subepithelial Tcells)

can effect D cell which affects T cell or T cell directly 

HIV - Course of infection

• acute - 2-4weeks - HIV spreads throughout the body - attacks CD4 cells - highly contagious

• chronic/clinical latency stage - may show no symptoms - antibodies detected - low risk of transmission if taking antiretrovirals

• AIDS - CD4 depleted - CD4 count of less than 200c/ml

Acute HIV infection symptoms

• fever

• malaise

• sores in mouth/oesophagus

• thrush

• myalgia

• neuropathy

• vomiting/nausea

Acquired Immune Deficiency Syndrome (AIDS) - infections and malaignancies

CD4 T cell numbers are reduced -> opportunistic infections

Infections:

• Parasites (Toxoplasma spp, Cryptosporidium spp, Leishmania spp)

• Bacteria (Mycobacterium tuberculosis, Salmonella spp)

• Fungus (Pneumocystis carinii, Cryptococcus neoformans, Candida spp)

• Viruses (Herpes simplex, Cytomegalovirus, Varicella zoster)

Malignancies:

1. Kaposi’s sarcoma (Human Herpesvirus 8 /Kaposi sarcoma-associated herpesvirus)

2. Non-Hodgkin’s lymphoma (including Burkitt’s lymphoma)

3. Primary CNS lymphoma

4. Invasive cervical cancer

5. Increased rates of other cancers