Immunodeficiency

Immunodeficiency, as you can guess from the name, is a deficiency in one or more components of the immune system. There are two main categories: Primary deficiency, which is from a genetic or congenital issue, and secondary deficiency, which is much more common and is acquired through disease (e.g. HIV/AIDS), burns, chemotherapy, immunosuppressive drugs and so on. Blood counts and other tests to detect Ig levels and efficacy of immune response can be used to screen for immunodeficiency diseases.

Primary Innate Immunity Defects

Chronic Granulomatous Disease

I've already covered chronic granulomatous disease (CGD) in an earlier post. Essentially it's a defect in phagocyte oxidase, which means no production of reactive oxygen intermediates (ROIs), which means impaired killing of microbes.

Complement Immunodeficiency

Complement immunodeficiency is just what it says on the box: a deficiency of complement, which I've covered in greater detail in an earlier post. Without complement, functions involving complement such as immune complex clearance, inflammation, phagocytosis and lysis are all impaired.

Primary Adaptive Immunity Defects

DiGeorge's Syndrome

DiGeorge's Syndrome got a cameo appearance here, but now I'm going to cover it in more detail! DiGeorge's Syndrome is essentially where the thymus fails to develop. This can be partial or complete, leading to low or no T-cells. People with this condition are extremely susceptible to many infections. Even live vaccines can be life-threatening towards these patients.

Bruton's disease (X-linked agammaglobulinaemia)

In Bruton's disease, B-cells fail to mature. This is due to a defect in Bruton tyrosine kinase (BTK), which phosphorylates a lot of proteins important in B-cell development. Like DiGeorge syndrome, this can be partial or complete, leading to low or no B-cells. This, in turn, causes lymph nodes to be small and antibodies to be absent in the blood. Symptoms usually do not show up until around 3 months of age, as the child will have received IgG from their mother which protects them for the first few months of life.

Hyper-IgM Syndrome

In this syndrome, there is a mutation in the CD40 ligand molecule on T-cells, preventing T-cell dependent B-cell activation (a process which I've described in greater detail in an earlier post). This, in turn, leads to defects in other processes, such as class switching. As class switching is affected, most B-cells remain producing IgM. People with this condition may be susceptible to certain microbes, such as Pneumocystis carinii.

Common Variable Immunodeficiency (CVID)

In CVID, there are reduced levels of IgG and IgA, due to variable failures of B-cell maturation into plasma cells. This, in turn leads to reduced antibodies (hypogammaglobulinaemia- low levels of gamma globulins). This can be treated via intravenous immunoglobulins.

ADA (Adenosine Deaminase) Deficiency (ADA)

In ADA, there is a deficiency in the enzyme adenosine deaminase, which usually helps to break down deoxyadenosine. Deoxyadenosine is toxic to lymphocytes, so its accumulation leads to reduced numbers of B and T cells. ADA has been identified as an autosomal recessive disorder, so you need both copies of the gene to inherit it.

Severe Combined Immunodeficiency Diseases (SCID)

SCID, as I've mentioned before, is a disease involving mutations in the RAG1 and RAG2 genes responsible for formation of BCRs and TCRs. Hence, a hallmark of this disease is a failure of B- and T-cell maturation, leading to increased susceptibility of many infections past ~3 months (when the IgG from the mother has gone). Live vaccines also cannot be given to these patients. Fortunately, SCID can be treated with a bone marrow transplant with working RAG1 and RAG2 genes. Once these working genes have been reintroduced, RAG1 and RAG2 can be produced, allowing for production of both B- and T-cells. Transplanted bone marrow can stay around for life.

Secondary (Acquired) Immunodeficiency

We will only be learning about one example of secondary immunodeficiency, which is that caused by HIV (Human Immunodeficiency Virus). HIV is a nasty bug, as it infects the macrophages and T-helper cells of our immune system. During the "first wave," gp120, one of the glycoproteins of the HIV virus capsid, binds to CD4 and CCR5 on the macrophage cell surface. (CCR5 is a ligand for MIP chemokine, MIP being short for "macrophage inflammatory protein.") During the next wave, gp120 binds to CD4 and CXCR4, the latter being a chemokine receptor for CXCL12. Another important glycoprotein is gp41, which is required for virus fusion and internalisation.

In the early stages of HIV, the patient may or may not experience a "flu-like disease" as they begin to mount an adaptive immune response to the attack. This brings down levels of the virus in plasma, but unfortunately not forever. As I've mentioned in a post for PHAR2210, HIV can mutate very rapidly, leading to not only drug resistance, but resistance to antibodies and cytotoxic T-cells. The immune system is unable to keep up, especially since HIV is destroying it at the same time. After 2-12 years in a latent phase, where the patient shows no symptoms, the immune system eventually gets overwhelmed and the patient can become very ill. Eventually, T-helper cell levels drop to the point where the patient is considered to have AIDS.