IMMUNODEFICIENCIES

1.            Immunodeficiency diseases

a.            Immunodeficiencies occur when one or more components of the immune system is defective.

b.            Immunodeficiency may be:

i.            inherited: usually x-linked recessive genetic disorders.

ii.            acquired: infection by HIV.

c.         The commonest cause of immune deficiency worldwide is malnutrition; however, in developed countries, most immunodeficiency diseases are inherited.

d.            Immunodeficiency can occur in any of the 4 major components of the immune system:

i.          B cells

ii.          T cells

iii.            complement

iv.            phagocytes

e.            Clinically, recurrent or opportunistic infections are commonly seen.

f.            Recurrent infections with pyogenic bacteria, e.g. staphylococci, indicate a B cell deficiency, whereas recurrent infections with certain fungi, viruses or protozoa indicate a T cell deficiency.

2.            Important congenital Immunodeficiencies

3.            Correction of Genetic defects

a.         It is possible to correct the defects in lymphocyte development that lead to SCID by replacing the defective component by bone marrow transplantation.

b.         The major difficulties in these therapies result from MHC polymorphism.

c.         To be useful, the graft must share some MHC alleles with the host:

i.          the MHC alleles expressed by the thymic epithelium determine which T cells can be positively selected.

ii.          when bone marrow cells are used to restore immune function to individuals with a normal thymic stroma, both the T cells and the antigen-presenting cells are derived from the graft.

iii.            therefore, unless the graft shares at least some MHC alleles with the recipient, the T cells that are selected on host thymic epithelium cannot be activated by graft-derived antigen-presenting cells.

d.         Danger of graft-versus-host disease can be overcome by depleting the donor bone marrow of mature T cells.

e.         Gene therapy involves extracting a sample of the patients own bone marrow, inserting a normal copy of the defective gene into them, and returning them to the patient by transfusion.

4.            Acquired Immunodeficiency Syndrome

a.         HIV infection:

i.          AIDS is characterized by susceptibility to infection with opportunistic pathogens, or the occurrence of an aggressive form of kaposi’s sarcoma, accompanied by a profound decrease in number of CD4 T cells.

ii.          the agent responsible for AIDS is the human immunodeficiency virus (HIV).

iii.         there are two types of HIV, HIV-1 and HIV-2, which share 40% of their genome.

iv.         most AIDS worldwide is caused by HIV-1 while HIV-2 is endemic in West Africa and is now spreading in India.

b.            Transmission of HIV:

i.          the initial infection with HIV generally occurs after transfer of bodily fluids from an infected person.

ii.          the virus is carried in infected CD4 T cells and macrophages, and as a free virus in blood, semen, vaginal fluid, or milk.

iii.         it is most commonly spread by sexual intercourse, contaminated needles used for intravenous drug delivery, and the therapeutic use of infected blood or blood products.

iv.         an important cause of virus transmission is from an infected mother to her baby at birth or through breast milk; this can be largely prevented by treating infected pregnant women with AZT.

c.         Primary infection:

i.          primary infection with HIV is usually asymptomatic but sometimes causes a flu-like illness with an abundance of virus in the peripheral blood and a marked drop in the level of circulating CD4 T cells.

ii.          the acute viremia is associated with activation of CD8 T cells, which kill HIV-infected cells, and subsequently by antibody production, or seroconversion.

iii.            seroconversion usually occurs 2-12 weeks after initial infection and often accompanies or follows a glandular fever-like illness (fever, fatigue, lymphadenopathy, rash).

d.         Course of infection:

i.            incubation period from acute infection to seroconversion is usually between 2 and 12 weeks but may take up to six months.

ii.          most patients who are infected with HIV will eventually develop AIDS after a period of clinical latency which usually last 8-10 years, but can occasionally occur within a few months of seroconversion.

iii.         this period is not silent, for there is persistent replication of the virus, and a gradual decline in function and number of CD4 T cells until patients have too few CD4 cells left.

iv.         the pattern and rate of progression of HIV disease varies significantly between individuals and appears to be dependent upon the person’s age, sex, general health and the mode of infection.

e.            Virology of HIV:

i.          HIV is an enveloped retrovirus.

ii.          each virus particle has two copies of an RNA genome, which are transcribed into DNA in the infected cell and integrated into the host cell chromosome.

iii.         the RNA transcripts produced from the integrated viral DNA serve both as mRNA to direct the synthesis of the viral proteins and later as the RNA genomes of new viral particles, which escape from the cell by budding from the plasma membrane.

f.            Replication of HIV:

i.          one of the proteins that enters the cell with the viral genome is the viral reverse transcriptase, which transcribes the viral RNA into a complimentary DNA copy.

ii.          the viral cDNA is then integrated into the host cell genome by the viral integrase, which also enters the cell with the viral RNA.

iii.            replication of HIV is observed in both lymphoid and mucosal tissue.

iv.            macrophages, which are also infected by HIV, is able to harbor the virus without being killed by it and is an important reservoir of infection.

v.         during viral replication, signs of disease are usually absent in a clinically latent asymptomatic period.

g.         The entire HIV genome consists of nine genes flanked by long terminal repeat sequences (LTR) which are required for integration of the provirus into the host cell DNA and contain binding sites for gene regulatory proteins.

h.            Genome of HIV:

i.          gag gene encodes structural proteins of the viral core.

ii.          pol gene encodes the enzymes involved in viral replication and integration.

iii.         env gene encodes the viral envelope glycoproteins, gp120 and gp41.

I.          Life cycle of HIV in CD4 T cells:

i.          virus particle binds to CD4 on T cells; viral envelope fuses with cell membrane allowing viral genome to enter the cell.

ii.          reverse transcriptase copies viral RNA genome into double-stranded cDNA.

iii.         viral cDNA enters nucleus and is integrated into host DNA.

iv.         T-cell activation induces low-level transcription of provirus.

v.         RNA transcripts are multiply spliced, allowing translation of early genes tat and rev.

vi.         Tat amplifies transcription of viral RNA while rev increases transport of singly spliced or unspliced viral RNA to cytoplasm.

vii.        the late proteins, gag, pol and env, are translated and assembled into virus particles which bud from the cell.

j.          High mutation rate of HIV:

i.          the rapid replication of HIV contributes to the very high mutation rate that generates the many variants of HIV that arise in a single infected patient in the course of infection.

ii.            replication of a retroviral genome depends upon two error-prone steps.

iii.         reverse transcriptase lacks the proofreading mechanisms associated with cellular DNA polymerases and the RNA genomes of retroviruses are copied into DNA with relatively low fidelity.

iv.         the transcription of proviral DNA into RNA copies by the cellular RNA polymerase is a low-fidelity process too.

v.         a rapidly replicating persistent virus that is going through these two steps repeatedly in the course of an infection can thereby accumulate many mutations, and numerous variants of HIV.

k.         HIV kills CD4 T cells by:

i.          direct viral killing.

ii.            inducing apoptosis in infected cells.

iii.         immune response of CD8 cytotoxic T cells.

5.            Clinical Presentation of AIDS

a.         AIDS Related Complex (ARC):

i.            symptoms: night sweats, weight loss, fever, diarrhea, malaise, fatigue.

ii.            infections: hairy leukoplakia, herpes simplex, herpes zoster, warts, oral candidiasis, chronic lymphadenopathy, hepatosplenomegaly, molluscum contagiosum.

b.            Persistent Generalized Lymphadenopathy (PDL):

i.            frequently the first sign of infection with HIV.

ii.          defined as the presence of enlarged nodes, at least 1cm in diameter in two or more extra-inguinal sites for at least 3 months in absence of any illness or medication known to cause enlarged nodes.

iii.         patients usually still feels well, HIV replication appears to increase and CD4+ cell counts start to fall below normal levels.

c.         Central Nervous System:

i.            encephalitis due to herpes virus and atypical mycobacteria and toxoplasma.

ii.          CMV retinitis

iii.            meningitis due to Cryptococcus neoformans.

d.         HIV neurological diserase: encephalopathy, myelopathy (spastic parparesis) and peripheral neuropathy.

e.            Gastrointestinal:

i.          sore mouth, dysphagia, diarrhea and weight loss.

ii.            oropharynx: candidiasis, herpes simplex ulceration, ulcers, hairy leukoplakia.

iii.            esophagus: candidiasis.

iv.         small bowel: diarrhea and weigh loss due to crytosporidium, Isopora bellia, a typical mycobacteria.

v.         large bowel: diarrhea due to cryptosporidium, herpes simplex, CMV.

vi.         anus: perianal ulceration due to HSV.

f.            Pulmonary:

i.            Pneumocystis carinii pneumonia: malaise, fever, unproductive cough, retrosternal chest pain, increased shortness of breath.

ii.            tuberculosis due to Mycobacterium tuberculosis.

g.            Hepatitis: typical syndromes include abdominal pain and fever with raised liver enzymes, due to viral, atypical mycobacterial, toxoplasma and fungal infections.

h.         Skin: HSV, VZV, molluscum contagiosum, tinea.

I.            Secondary cancers: Kaposi’s sarcoma, lymphoma.

6.            Laboratory Diagnosis of HIV Infection

a.            Detection of virus:

i.          PCR can detect very low levels of HIV DNA integrated into host cells.

ii.          virus can be cultured from lymphocytes obtained from HIV infected people.

iii.         such techniques are expensive, time consuming and not extensively used.

b.         HIV antibody tests:

i.          time lag between acute infection and antibody presence may be up to six months.

ii.          ELISA are first antibody tests.

c.            Confirmation tests:

i.            confirmation of positive results by Western blot is mandatory.

ii.          a positive result generally requires the presence of bands at p24, p31, gp41 and gp120 or gp160.

d.            Monitoring:

i.          p24 is detectable soon after infection; it usually disappears within two months of antibody titres rise.

ii.          p24 frequently reappears later in the disease as viral antigenaemia exceeds antibody production.

iii.         a decline in p24 antibody may be an early indicator of progression to clinical HIV infection.

iv.         non-specific markers of HIV infection: CD4+ counts.

7.            Management of HIV Infection

a.         Specific anti-HIV therapy:

i.            Zidovudine (AZT) is first line therapy used to retard progress of disease.

ii.          ddC is used in combination with zidovudine for patients with advanced disease who have demonstrated significant deterioration whilst on zidovudine.

iii.            protease inhibitors which inhibit the breakdown of HIV-made mRNA are employed too.

b.            Secondary Cancers:

i.            Kaposi’s sarcoma: excision, radiotherapy, chemotherapy, interferon.

ii.            Lymphoma (usually non-Hodgkin’s): chemotherapy, irradiation.

c.            Secondary infectious disease:

i.            Pneumocystis carinii pneumonia: high dose co-trimoxazole, pentamidine isethionate.

ii.            Mycobacterium tuberculosis: quadruple chemotherapy, ansamycin.

iii.            Candidiasis: nystatin, amphotericin B, ketoconazole, fluconazole.

iv.            Systemic fungal infections: amphotericin B, fluconazole, clotrimazole.

v.         Herpes simplex/zoster: acyclovir.

vi.         CMV: ganciclovir, foscarnet.

vii.            Crytosporidiosis: spiramycin

viii.            Toxoplasmosis: pyrimethamine and sulphadiazine or clindamycin.