Immunodeficiency Diseases

Ziad Elnasser, MD, Ph.D

Immunodeficiency Disorders
Primary (inherited) vs Secondary(external) Genetics. Polymorphism. Polygenic factors. Infection and tumor types. Diagnosis and Treatment.

Infections provide Clues to the Type of Immunodeficiency

When healthy people get infected? Repeated and unusual infections.

Encapsulated bacteria and Ab deficiency. Staph, G-, and fungi with Phagocytes. Neisseria and Complement. Intracellular bacteria, viruses (including oncoviruses), protozoa with T cell deficiency.

Causes of Primary Immunodeficiency

Mutations SCID (INF receptor, rag, Zap70)

Autosomal (Rag) X-linked ( chain, hyper IgM syndrome) deaths in maternal uncles). Digeorge syndrome (chromosomal translocation)

Polymorphism: Many allelic forms of the same gene, eye color, HLA, cytokines and HIV, MBL, HbS and Malaria. Polygenic disorders: Genetics and environment (CVID)

IgA deficiency (the most common) and celiac disease. Recurrent infections in the respiratory tract. Autoimmune diseases. Anti-rheumatic and anticonvulsant drugs. Specific antibody deficiency.

Diagnosis
Recurrent unusual infections. Failure to thrive, diarrhea, unusual rash and family history of neonatal death. Low level of total lymphocytes. Antibody deficiency comes later. Exclude secondary causes. Ab levels, C, phagocytes. Genetics testing ,carriers.

Treatment

Aim to prevent infection. In mild cases antibiotics prophylaxis. Ig replacement therapy, differ from Ig immunosuppression. Prions risk. Stem cell trasplantation in SCID. No live vaccines. Prophylaxis against PCP. Gene Therapy: Identify the mutation first. Regulate inserted gene. Safe gene delivery. Insertional mutagenesis concern. Does not work in older children.

Secondary Immunodeficiency Diseases

Secondary Immunodeficiency
HIV. Extreme of age. Drugs. Malignancy. Nutrition. Causes infection and malignancy.

HIV infection
>60 millions, 3m die/y, 1/2m children. Virus structure and pathophysiology. Mechanism of antiviral drugs, vaccines? Entry

Retrovirus structure. Envelope proteins role (Gp 120, Gp41). Role of CD4 and their location. CCR5 and CXCR4 role ,Sexual vs non.

Reverse transcription: So diverse. HIV latency and transcription.

The Immune Response to HIV

Highly infectious virus. Long latency and infectivity. Macrophages produces INF- not effective Abs produced used for Dx, not effective. Abs against exposed parts effective, T cells. CTLs are not effective. >105 viruses, antigen variation and Abs can,t keep up. Apoptosis.

The clinical Features of HIV infection

HIV seroconversion illness, more CCR5 damage less CD4 cells. Asymptomatic stage of HIV, balance between viral producion and T cell production. Opportunistic infections, fall of CD4 cells.

Factors Affecting Outcome of Infection

Genetic factors, polymorphism in CCR5 R. HLA heterozygous advantage.

Vaccines:
Abs does not have beneficial effect. Only against exposed epitopes, and IgA. CTL response by recombinant vaccines. Genetic variations among ethnic people.

Treatment

Highly active antiretroviral therapy (HAART), combination of drug Rx.

RT inhibitors: Nucleoside analogues. Protease inhibitors. Fusion inhibitors.

Toll like receptor binding drugs. IL-2 with HAART and sterilizing Immunity.

Other secondary Immunodeficiencies

Extremes of age.

Young: Nave cells, Low Abs. Aging immune system: memory cells, replicative senesence, CMV oligoclonality, less vaccine response, infection, malignancy.

Stress: Infection: Malaria, measles, Rubella, Drugs: Corticosteroids, cytotoxic drugs, immunosuppressive drugs, anticonvulsants. Nutrition: Zinc and Mg++ deficiency, B-cell malignancy. Kidney disease: Nephrotic syndrome, diarrhea.