Primary Immunodeficiency

Primary immunodeficiencies are congenital disorders of the immune system. Medicine now knows more than 300 different clinical pictures, many of them are among the rare diseases. More about the symptoms, causes, and therapy of primary immunodeficiency.

Definition

Primary immunodeficiencies are congenital disorders of the immune system, which can also be hereditary. The children are born with an immune system that cannot work properly or is incorrectly designed. As a result, those affected are exposed to an increased risk of infection. Medicine now knows more than 300 different clinical pictures that are caused by primary immunodeficiency. Some of the immune defects are so pronounced that the affected children cannot survive the first year of life without stem cell therapy. The symptoms can also only develop in the course of childhood or adulthood. Or they are recognized as an immunodeficiency after years of a doctor odyssey. Because most primary immune defects are very rare – and therefore not even known to many medical professionals. Some immunodeficiencies are treatable, others cannot. The most promising treatment options for primary immune deficits are drug therapy with immunoglobulins and stem cell transplants.

The Function Of The Immune System

Most people know the immune system as a protection against infection. The defense against pathogens such as bacteria, viruses, fungi, or parasites is only one task of the body’s own defense. A healthy immune system also fights cancer cells, for example, or protects the body cells from harmful influences. A defective immune system, on the other hand, triggers allergies, rheumatic diseases, or other autoimmune diseases.

The immune system is an extremely complex system. The most important actors in this system include antibodies, B lymphocytes, T lymphocytes, and their subgroups, as well as natural killer cells.

Antibody

Antibody is a slang term for the so-called immunoglobulins. This is a large group of special proteins that the immune system produces after contact with pathogens or their components. Immunoglobulins are produced by the B lymphocytes.

B lymphocytes

B lymphocytes (B cells for short) are a specific group of white blood cells called leukocytes. They play a central role in the immune system, as they are involved in the recognition of foreign germs and substances on the one hand and in the formation of antibodies on the other. B lymphocytes – like all other cells – arise from stem cells in the bone marrow. In the development process from the stem cell to the antibody-producing B-lymphocyte, a wide variety of genetic defects can cause various diseases. Two examples are B-cell non-Hodgkin lymphomas and B-cell lymphoblastic leukemia.

T lymphocytes

T lymphocytes (also called T cells) are another type of white blood cell called leukocytes. These defense cells are also formed in the bone marrow and, like the B cells, belong to the acquired immune system. They experience their actual “training” in the thymus gland, for example, to fight fungal or viral infections. To do this, T lymphocytes control the cell membranes of cells. However, T lymphocytes are not able to recognize pathogens on their own. To do this, they rely on antigen-presenting cells such as B lymphocytes. As soon as these cells present pathogens, T lymphocytes become active.

T Helper Cells

The T-helper cells are a subgroup of the T-lymphocytes. They recognize presented antigens and decide whether the body’s own defense system needs to be active. If so, the T helper cells pass on information to the killer cells via so-called receptors. These then destroy the infected or damaged cells.

T Suppressor Cells

Another important subgroup of T lymphocytes is T suppressor cells. After successfully fighting the pathogens, they suppress the active immune system. This prevents excessive immune reactions against healthy body tissue (so-called autoimmune reactions).

T Memory Cells

Memory T cells also belong to the T lymphocytes. These have a preventive effect by storing information about the pathogens being controlled. As soon as the same pathogen penetrates the body again, the “knowledge” of the T memory cells enables rapid defense measures. This often happens so quickly that an infection is not even noticed.

Primary Immunodeficiency

Phagocytes

Phagocytes are specialized cells of the immune system, which are also known as phagocytes or macrophages. They belong to the innate defense system. Scavenger cells envelop identified foreign bodies such as pathogens or cell debris and break them down. Like B and T lymphocytes, phagocytes belong to the white blood cells, the leukocytes. Subtypes of leukocytes are precursor immune cells such as monocytes (which transform into macrophages) and granulocytes (which in turn can be divided into three subgroups).

Natural Killer Cells

Natural killer cells are another subgroup of white blood cells that do not belong to either the B or T lymphocyte group. Like phagocytes, they are part of the innate immune system. Natural killer cells got their name because they can trigger the programmed cell death of these cells, especially in virus-infected or degenerate cells (cancer). Doctors refer to programmed cell death as apoptosis.

Frequency

Fortunately, primary immunodeficiencies are very rare. There is about 1 case of congenital immunodeficiency for every 10,000 births. In Germany, there are currently an estimated 100,000 people with PGD. About 70 percent of the cases are immune deficiencies with a lack of antibodies.

Since the total number of sufferers is spread over more than 300 diagnoses, many of the primary immunodeficiencies are rare diseases, orphan diseases.

Symptoms

The symptoms of primary immunodeficiency can vary widely. This mainly depends on the type and severity of the immune deficiency. In the case of severe immune deficiencies, the first symptoms often appear in the first weeks and months after birth. In the case of milder innate immune diseases, the symptoms can initially be masked by the mother’s so-called nest protection and breastfeeding. The nest protection is created by immunoglobulins that are transferred through the placenta to the embryo during pregnancy and birth. Maternal antibodies are also passed on to the infant during breastfeeding. The nest protection is thus positively supported with breast milk. In addition, there are immunodeficiencies that only show up during puberty or in young adults up to the age of 25.

Warning Signs Of Primary Immunodeficiency

Beyond the varied – and thus sometimes very difficult to recognize – symptoms of primary immune deficits, there are at least a number of warning signs that suggest the suspicion of a congenital immune deficiency:

    • Primary immunodeficiencies in first-degree relatives (parents or siblings)
    • Increased susceptibility to serious infections: 2 or more cases of meningitis, bone inflammation, pneumonia, joint inflammation, blood poisoning (sepsis), or sinusitis each year.
    • More than 8 purulent otitis media per year
    • Antibiotic therapy ineffectiveness for more than 2 months
    • Complications after vaccination with life vaccines such as rotaviruses
    • Failure to thrive with no other apparent cause
    • Noticeable skin and mucous membrane diseases such as persistent skin fungal infections or skin inflammation (erythema) in newborns and infants
    • Chronic diarrhea.

Causes

Primary immune deficiencies are innate, so the cause is a defective genetic material. How these DNA defects arise is largely unclear. The World Health Organization divides primary immunodeficiencies into 8 groups according to their causes:

    • Combined immunodeficiency, which affects several parts of the immune system
    • Immunodeficiencies, which are mainly characterized by a lack of antibodies
    • Immunodeficiencies associated with defective T lymphocytes
    • Other well-defined immunodeficiency syndromes
    • Immune defects with lymphoproliferative disease
    • Immunodeficiency associated with or as a result of another disease
    • Complement defects
    • Defects of the granulocytes and macrophages

Diagnosis

Most primary immune deficiencies are difficult to diagnose and often take many months or years to diagnose. First of all, this is due to the fact that the symptoms are usually very unspecific. In the case of recurring severe infections (see also warning signs), the suspicion could be obvious. However, many immune defects are so rare that doctors are barely aware of these rare diseases. For recurring severe infections and other warning signs, the diagnosis should therefore be made at an Immune Diseases Center.

Treatment

Primary immunodeficiency therapy is primarily medicated and depends on the type and severity of the immunodeficiency.

Acute drug therapy and prophylaxis

In the case of minor immune deficits, it can be sufficient to treat acute infections with antibiotics, antiviral agents, or antifungal agents, as in a healthy person. As a rule, children with weak immune deficiencies also receive these drugs permanently in order to better prevent possible infections.

Antibody replacement treatment

Many immune deficiencies cause a lack of antibodies. These immunoglobulins can be replaced by drug therapy. Depending on the type of antibody, they are injected under the skin at regular intervals or given as an infusion. Antibody replacement treatment is usually necessary for life.

Stem cell transplant

A stem cell transplant may be the method of choice for certain, particularly severe immunodeficiencies. During this procedure, stem cells are transferred from the bone marrow of healthy donors. This therapy option is by no means available to all those affected. There are several reasons for this. First of all, not all forms of primary immune deficiency can be treated with a stem cell transplant. Then children or adolescents must be in a state of health that allows the stressful transplant procedure at all. In addition, a donor has to be found whose stem cells match the patient. The decision about the possibility, benefits, and risks of a stem cell transplant can therefore only be made on an individual basis.

Gene therapy

Gene therapeutic approaches for the treatment of primary immune deficiencies are currently still at an experimental stage. The aim of the experiments is to replace the faulty section of the genetic material with healthy genes for immune cells.

Forecast

A general prognosis of primary immunodeficiencies is not possible in view of the diversity of the diseases. Basically, however, the earlier the diagnosis and treatment, the better the chances of survival. Many forms of antibody deficiency can be treated by immunoglobulins in such a way that life expectancy equals that of healthy people.

Prevention

Since primary immune deficiencies are innate, these diseases cannot be reliably prevented.