This article aims to help understand immune problems encountered in ataxia telangiectasia and presented in other sections of this chapter.

Immunity

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Immunity can be defined as the ability to recognize "self", that is to say every single part of my body, and to reject the "non-self", every foreigner who wants to enter it or develop abnormally. We call these intruders antigens.

There are three lines of defense:

• the first two are called innate or non-specific because they act regardless of the nature of the aggression.
• the last is called acquired because it is developed according to the type of aggression.

Recognition principle

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The self is recognized through the major histocompatibility complex (MHC),called HLA (Human Leukocyte Antigen) in humans: cells have unique surface proteins to differentiate self from nonself.
Note that in humans, the brain has its own immune system separate from the rest of the body.

Types of aggression

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Agressions may be:

• Physico-chemical (chemical, climatic, mechanical, ....)
• Due to other organisms (which creates infection) viruses, bacteria, fungi, yeasts, ...

They are permanent.

Defence line 1 : skin and mucous

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They both offer a barrier against micro-organisms:

• The skin is covered with keratin resisting to bacterial enzymes. There are also hair and eyelashes.
• The high impermeability of the very tight mucosal cells protects the respiratory, digestive, respiratory or genito-urinary ways. Some mucous membranes are also covered with a protective film, the mucus, which is evacuated with the foreign bodies "captured" thanks to cilia.
• In tears and saliva contain lysozyme which destroys the cell wall of many bacteria.

Defence line 2: innate immunity

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The second line consists of cellular and chemical defenses:

Cells have passive defense systems. They are chemical and biochemical enzymes, fatty acids, lactic acid, intestinal flora, pH, etc. ... which create such an hostile environment that number of antigens can't survive.

When aggression occurs by injury, damaged cells release chemical mediators that will initiate the inflammatory response: expansion and greater permeability of vessels to rapidly bring the necessary elements to repair and the fight against infections. The area becomes "red" because of the blood flowing.

These chemical mediators will also attract phagocytes (all white blood cells or leukocytes: macrophages, neutrophils and eosinophils), which are responsible for destroying infected cells, microorganisms and foreign substances by eating them (phagocytosis). Note that phagocytes adhere more easily to foreign particles when these are coated with complement proteins and antibodies (see below).

Defence line 3: Specific or acquired immunity

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The third line of defense is to develop a personalized response in front of the aggression and memorize it.

This response may take several days before being effective. It is much faster, thanks to the faculty of memory, if the antigen has already tried to invest the body before and is recognized.

Two types of answers are developed from a "specific network", the lymphatic system and the bone marrow:

• Cellular immunity gets rid of the infected cells
• The humoral immunity is to remove free antigens in the body

The lymphatic system

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• Primary lymphoïd organs: the bone marrow and thymus for the lymphocytes maturation (see below)
• Secondary lymphoid organs: lymph nodes, spleen, tonsils and lymphoid tissues present in the mucous membranes. The lymphatic system, by bringing foreign bodies to these secondary organs, detects, recognizes and activates the mass production of T and B cells needed for the specific response. This explains for example that the closest lymph nodes to the infection swell.

Cellular immunity

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The cellular immune system is targetting the body's cells that are infected by viruses or bacteria, and cancer cells.

The action is carried out by T cells that are derived from stem cells from bone marrow and mature in the thymus (T for thymus). There are two families of T lymphocytes:

• Cytotoxic T lymphocytes (T_C) test cells surface through their receptors. If they are not recognized, the cell is regarded as foreign and destroyed by chemical perforation of the membrane.

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  Helper T cells (T_H) interact with macrophages and produce molecules, cytokines (or interleukins) inducing proliferation of B and T lymphocytes and thus a strong immune response.

Humoral immunity

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The humoral immune responses can be triggered by:

• Free antigens (antigenic molecules, fragments of membranes)
• Antigens carried by cells (bacteria, infected red blood cells ,...)

These responses involve circulating antibodies: immunoglobulins or antibodies.

What are antibodies? ?

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Antibodies are complex proteins for detecting antigens in a specific manner. .

These are glycoproteins formed in a Y shape and:

• Variable parts at the end of each arm of the Y forming the recognition sites of the intruder and allowing the antibody to attach to it.
• Constant parts allowing it to be recognized by the body cells

They are produced by plasmocytes, B lymphocytes that have evolved, marrow stem cells whose maturation also ends in the marrow.

Function of antibodies

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Thus equipped, each antibody may:

- Neutralize free antigens:

• Neutralize toxins released by bacteria and thus protect their targets.
• Agglutinate and precipitate antigens (antigenic molecules, fragments of membranes). This option reduces the number of infectious units and, by presenting them in larger complexes and more recognition factors, facilitates their treatment by phagocytosis.

- Clinging to antigens
on the surface of the microorganisms membranes (bacteria, infected red blood cells ...) to:

• Block the binding capacities of these antigens on the surface of healthy cells or mucous membranes. It is the role of IgA.
• Make immunocompetent cells (macrophages, NK cell killer ,...) recognize labeled antigens which will be eliminated by phagocytosis. It is opsonization. This usually involves the complement (see below). It is the role of IgG and IgM.
• Activate the complement

The different antibodies

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Antibodies are divided into classes or isotypes, depending on the structure of their constant parts: IgG, IgA, IgM, IgE and IgD.
Moreover, one can classify a population of antibodies according to his ability to recognize one or more antigen binding sites. This is called respectively monoclonal and polyclonal antibodies.

Distribution of the roles of immunoglobulins (Ig) class:

• IgA: mainly in secretions such as saliva, intestinal juices, sweat and breast milk. The main role of IgA is to prevent pathogens from binding to the cell and more specifically to the covering cells of the mucous membranes and the epidermis (outer layer of skin).
• IgM: secreted during the first contact of the organism with an antigen. This is the first class of immunoglobulins released by a variety of white blood cells: plasmocytes. The presence of IgM in the blood indicates a current infection.
• IgE:they are also secreted by plasmocytes in the skin, gastrointestinal tract, tonsils and respiratory tract. This variety of immunoglobulins is connected to mast cells and basophils (white blood cell varieties) by a rod. Upon capture of an antigen, immunoglobulin triggers the release of product involved in the inflammatory response and histamine entering the allergic reaction. IgE concentrations increased in case of severe allergy and parasites are present in the gastrointestinal tract.
• IgG:the most abundant (75 to 80% of circulating antibodies). They are made when a contact with an antigen occurs. They protect the body against bacteria, viruses, and toxins circulating in the blood and lymph. On the other hand, they quickly fix the complement (see above, "complement"). They also participate in the memory response on which is based the mechanism of vaccination. Finally, immunoglobulin G cross the placenta and thus provide the fetus with a passive immunity.
• IgD: most often attached to the surface of B cells where they play a role in antigen receptor. They intervene in the maturation of lymphocytes, that is to say in the mechanism by which these white blood cells become effective.

Complement

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Complement is a set of non-specific proteins that are activated in cascade when the antibodies bind to antigens.
This cascade of reactions has four main effects:

• Activate the inflammatory response (see "defence line 2" above)
• Attract phagocytes (eating cells) at the site of infection
• Opsonization of cells presenting antigens (see above: "clinging to antigens).
• Lysis (membrane perforation) of microorganisms marked by the antibodies, in combination with them.

Immune system diseases

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The immune system may be faulty:

• by excess when attacking the body's own cells by poor recognition (these are autoimmune diseases).
• by default when allowing cancers and pathogens to develop (in the case of immune deficiency). This is the case in ataxia telangiectasia.

The ATM gene is central to the immune system.

The majority of patients with Ataxia Telangiectasia is immunodeficient, but not everyone.

Immune disorders in AT relate to antibodies and T and B lymphocytes, that is to say mainly acquired immunity, the one targeted by vaccines.

Weakened immune defenses

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The main consequence of immune deficiency in ataxia telangiectasia is a weakness against infectious agents..

Most patients with ataxia telangiectasia develop antibody responses against antigens, such as micro-organisms, but some of these responses may be affected, particularly the responses directed against the polysaccharides (large complex carbohydrates) on the surface of bacteria that causerespiratory infections..

These abnormal antibody responses may be associated with abnormal levels of circulating immunoglobulins. Thus, patients with AT may present in isolation or simultaneously the following deficiencies:

B cell deficiencies

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Deficiencies of B cells has implications in the production of immunoglobulins (or antibodies):

• A deficit or absence of IgA in 70% of patients with AT. If this is the only deficiency, most people show no significant symptoms.
• A deficit or an absence of IgE in 80% of patients.
• Deficiencies of IgG subclass, especially IgG2 and IgG4. The IgG2 are particularly important in the fight against encapsulated bacteria, bacteria coated with a protective shell that are the cause of many of ENT infections, bronchitis and pneumonia.
• The rate of IgM is usually normal.

At the opposite, 10-15% of patients with AT show immunoglobulin levels well above normal.

T cell deficiency

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The blood rate of T cells may be abnormally low. These abnormal T cells are generally associated with a small or immature thymus. The low rate of T cells does not always increase susceptibility to infection, but over time, this rate becomes smaller and smaller.

Cancer risk

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Finally, patients with ataxia telangiectasia have a higher risk of developing certain cancers, particularly cancers of the immune system, such as lymphoma and leukemia. (see chapter « cancer »)

Process of déficiency in AT

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All these deficits in Ataxia Telangiectasia have an explanation at the genetic level.

Indeed, in the chapter "ATM: DNA controller", we saw the essential role of the ATM protein in the repair of DNA double strand breaks (DSB) in the cells: in its absence the cells with DSB can't work but can still reproduce themselves. This is detrimental to healthy cells whose proportion decreases gradually. The functions for which they are scheduled to take place less efficiently, if at all: the body is weakened and aging is accelerated.

This applies to specific T cells and B cells (which produce specific antibodies: IgG among others).

But as for other body functions, evolution is slow, the expression of the anomaly is more evident on the response of acquired immunity, the one that fits and stores.

The reason lies in the process of individual and targeted response to millions of different attacks. The body responds by recombining for each attack a number of specific genes between them, thus multiplying the possibilities. The same "ingredients" are then assembled in different manners to create an active component perfectly adapted for attack.

It's a bit like a construction kit: with the same number of pieces you can make an incredible number of buildings ... And the more you have parts, the more this number increases exponentially.

But to build, man must first remove the parts from the packaging: for recombining genes, we must first break the DNA molecule that carries them and cause ... double-strand breaks (DSB), a normal body then repairs, not a patient with Ataxia Telangiectasia.

This is what happens especially on chromosome 7 for IgG and on chromosome 14 for specific T cell receptors (those who recognize the aggresions). In addition to immune problems, it also explains translocations (exchange of genetic material) between these two chromosomes found in laboratory among patients with AT and may help confirm the diagnosis.

To face

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Consult an immunologist.

Listen to your child. Neglect nothing and remain vigilant.

Avoid exposure to risk: do prevention.

shop helvetica, drugs sans-serif; font-size: 1em; background-color: #92d2dd; border: medium solid #333333; text-align: center;">Pulmonary complications are the leading cause of danger to patients with ataxia telangiectasia, pills ahead of cancer.

The immune problems are largely the cause.

Research is progressing rapidly to treatment.

You, parents, can make prevention.

Definitions

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The term "pneumonia" refers to lung diseases affecting the deep lung.
The bronchi may also be sick from immune deficiency and recurrent bronchitis, with the development of bronchiectasis (permanent bronchi expansion).

We are talking about:

• Pneumonia when the origin of the disease is suspected infectious (bacteria, fungi ...)
• Interstitial lung disease or infiltrative when an infectious cause has been eliminated by the microbiological investigations and lung disease is caused by inflammation. These are the alveoli and the supporting tissue of them that are reworked.
• Bronchiectasis when the bronchi have a chronically increased size.

Lungs and immunity

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We saw in chapter "Immunity and AT" that people with AT have a combined immunodeficiency, variable according to individuals, which affects both:

• Cellular immunity: B and T cells
• Humoral immunity: immunoglobulins IgA, IgE and IgG (mainly IgG2, IgG4).

Even the mucous membranes (the first barriers) are affected in ataxia telangiectasia (accelerated aging, IgA deficiency). Those of the respiratory system are therefore entry points for frequent and dangerous infections. They are favored by:

The deficit in T cells (the main actors of the specific -with memory- immune response ), which promotes:

• Viral infections: herpes virus group in particular (Cytomegalovirus: CMV)
• Fungal infections: Cryptococcus (yeast present in the dust), Aspergillus (fungus also present in the dust on construction sites for example)
• Infections with intracellular bacteria: mycobacteria (eg tuberculosis), salmonella and legionella.

The deficit in B cells and immunoglobulins, which promotes:

• Bacterial infections: pneumococcal, Haemophilus influenzae (responsible for various ENT infections and also pneumonia).
• Viral infections (see above).

These deficits may partly be made up by IV of immunoglobulin, but they do not cover the full spectrum of viruses and bacteria. To do this, and according to the deficit, the doctor may prescribe regular and permament medication to a particular antibiotic.

Risks

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These infections pose a risk of lightning extension and respiratory distress syndrome, irreversible if not caught in time. Even if remission, sequelae may remain with the development of bronchiectasis.

Bronchiectasis
It is the result of repeated lung infections. It is the chronic inflammation and airway obstruction by secretions that damage the bronchial wall.

Preventive treatment is based on immunoglobulin and antibiotics for infections. If bronchiectasis is established, treatment is based on chest physiotherapy (to help drainage of congested airways), in addition to preventive treatment that must be pursued.

This treatment is essential to slow the worsening of the lesions. Indeed, bronchiectasis, once installed, creates a vicious circle:

• Mucosa with ciliated cells lining the airways and allowing the natural drainage of secretions is not functional any more
• The sputum (mucus discharge) is less effective
• The mucus that has imprisoned the seeds is less well drained
• Germs stay put proliferate, thus promoting new infections

The clinical implications are:

• chronic coughing due to stasis (stagnation) of mucus
• secondary bronchial infections more frequent
• shortness of breath: the air is more difficult to travel due to bronchial obstruction and anatomical alterations

Interstitial pneumonia
Patients with AT may also develop an interstitial pneumonia (see definition at the beginning). It would be the consequence of abnormal lung repair facing the various assaults by deregulation of the immune system or lack of healing after lung aggression (infections, chemical oxidants ...).

The alveoli and the supporting tissue of these cells that are damaged. The final stage is fibrosis with consequent decrease in breathing capacity and a failure to transfer oxygen from the lungs into the blood. This complication is relatively rare (about 5% of patients) but serious, therefore it requires regular pneumologic monitoring to detect and treat it early.

Conclusion

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In the bleak picture of ataxia telangiectasia, pulmonary infections are the leading cause of mortality.

But paradoxically, they are also one of the few points on which the family circle can be influential(cf "pneumologist"). In two words: vigilance and prevention.

Moreover, if there are still many unknowns about how these infections destroy the lungs, investigation techniques are in constant progress and treatment are increasingly powerful.