What is immune deficiency syndrome occurring in adults


Immunodeficiency diseases

An immunodeficiency disease occurs when one or more components of the immune system are defective. A distinction is made between primary (hereditary or congenital) and secondary (acquired) immune deficiencies. Primary immune deficiencies are caused by inherited mutations in one of the many genes involved in or control of immune responses. To date, a good 150 primary immune deficiencies have been described that impair the development or function of immune cells or both areas. The clinical symptoms of these diseases are therefore very different. One common feature, however, is that young children experience repeated and often very severe infections. Secondary immune deficiencies are acquired as a result of other diseases, they arise secondarily as a result of external factors such as hunger or are a side effect of a medical intervention. Some forms of immunodeficiency primarily affect the immunoregulatory mechanisms. Defects of this type can lead to allergies, abnormal proliferation of lymphocytes, autoimmunity, and certain forms of cancer. These are discussed in other chapters. Here we want to concentrate primarily on the immune deficiencies that cause susceptibility to infections.

The primary immunodeficiency diseases can be differentiated based on the components of the immune system involved. However, since many components of the immune system are intertwined, a defect in one component can also impair function in other areas. Therefore, primary defects in innate immunity can lead to defects in adaptive immunity, and vice versa. Still, it makes sense to look at immunodeficiencies in relation to the major components of the immune system that are affected, as these produce certain patterns of infection and clinical symptoms. If one examines which infectious diseases are associated with a certain immune deficiency, it can be seen which components of the immune system are important for the reaction to certain pathogens. The hereditary immune deficiencies also make it clear how the interactions between the various immune cell types contribute to the immune response and to the development of B and T cells. Ultimately, these hereditary diseases can lead us to the defective gene and thus perhaps provide new information about the molecular basis of immune reactions as well as the necessary knowledge for diagnosis, good genetic counseling and possibly gene therapy.

A history of repeated infections suggests an immunodeficiency diagnosis

Immunocompromised patients are generally recognized by their clinical history of repeated infections with the same or similar pathogens. The type of infection indicates which part of the immune system is damaged. The repeated infection with pyogenic (pus-forming) bacteria allows the conclusion that the function of the antibodies, the complement system or the phagocytes is disturbed, since these parts of the immune system are important in the defense against such infections. On the other hand, indicate a permanent fungal infection of the skin, for example with Candida, or recurrent viral infections indicate that there is an immunodeficiency involving the T lymphocytes.

Primary immunodeficiency diseases are based on recessive genetic defects

Before antibiotics became available, most patients with inherited immune deficiencies died in infancy or early childhood because they were particularly susceptible to infection by certain pathogens. These hereditary diseases were not easy to identify, as many unaffected children also died as a result of infectious diseases. Most genetic defects that cause secondary (inheritable) immunodeficiency diseases are inherited recessively and many can be traced back to mutations in the genes of the X chromosome. Recessively inherited defects only lead to the disease if both chromosomes carry the faulty gene. Since men only have one X chromosome, all men who inherit an X-linked disease develop the disease. Women, on the other hand, usually stay healthy because of their second, unchanged X chromosome.

With the help of knockout procedures (Appendix I, Section A.35), various types of immune deficiency could be generated in mice, which quickly expanded our knowledge of how individual proteins contribute to the normal function of the immune system. Nevertheless, human immunodeficiency diseases still offer the best opportunity to gain insight into the normal reaction pathways of the immune defense against infectious diseases. For example, defects in the function of antibodies, the complement system or phagocytes increase the risk of being infected by certain pus-forming bacteria. This means that the host's reactions in defending against such bacteria normally take place in the following order: After the antibodies have bound, complement components are fixed, which enables the opsonized bacteria to be taken up and killed by the phagocytes. If a link is missing in this chain that leads to the killing of the bacteria, a similar immune deficiency always occurs.

The immune deficiencies also tell us something about the redundancy of the mechanisms with which the host fights infectious diseases. The first person (who happened to be an immunologist) to be found to have a hereditary defect in the complement system (a C2 deficiency) was healthy. This means that the immune system has a variety of measures available to protect against infection, so that a defect in one component of immunity can be compensated for by other components. Although there are numerous findings that a complement defect increases the susceptibility to pyogenic infections, not everyone with a complement deficiency suffers from recurring infections.

Fig. 13.1 shows examples of immune deficiency diseases. None of them are particularly common (a certain IgA deficiency is still the most common) and some are extremely rare. These diseases are described in the following sections and we have summarized them according to whether the underlying defect is in the adaptive or innate immune system.

Defects in T-cell development can lead to severe combined immunodeficiencies

The developmental pathways of the circulating naive T and B cells are summarized in Fig. 13.2. Patients with a defect in T cell development are susceptible to a wide range of pathogens. This shows that the differentiation and maturation of T cells plays a central role in adaptive immunity for practically all antigens. Since such patients show neither T-cell-dependent antibody reactions nor cellular immune responses and therefore cannot develop an immunological memory, they suffer from severe combined immunodeficiency (SCID ) .

The X-linked severe combined immunodeficiency (X-SCID ) is the most common form of SCID. The causes are mutations in the IL2RGGene on the human X chromosome that contains the γ-Chain (γc) of the interleukin-2 receptor (IL-2R). γc is part of all receptors for the cytokines of the IL-2 family (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21). Patients with X-SCID therefore show defects in the signaling of all cytokines of the IL-2 family, so that the T and NK cells cannot develop normally due to the lack of IL-7 and IL-15 signals (Fig. 13.2). The number of B cells, on the other hand, is normal, but due to the lack of support from the T cells, this does not apply to the function of the B cells. Most X-SCID patients are male. In women who carry the mutation, the precursors of the T and NK cells develop normally, which occur when the X chromosome is inactivated IL2RG-Have kept wild type alleles and produce a normal mature immune repertoire. X-SCID is also known as bubble boy disease - after a boy who had this disease for over ten years in a protective cover (bubble) lived before dying from complications from a bone marrow transplant. A clinically and immunologically indistinguishable type of SCID is due to an inactivating mutation of the tyrosine kinase Jak3 (Section 10.1007 / 978-3-662-56004-4_8 # Sec2), which physically γc binds and signals over γc-Transmits chain cytokine receptors. This autosomal recessive mutation also affects T and NK cell development, but B cell development remains unaffected.

Other immune deficiencies in mice made it possible to examine the functions of the individual cytokines and their receptors in the development of T and NK cells in more detail. In mice, for example, targeted mutations in the βc-Gen (IL2RB) determined the central function of IL-15 as a growth factor for the development of NK cells, as well as its importance for the maturation and migration of T cells. Mice with targeted mutations in IL-15 itself or in the α-Chains of the associated receptor also have no NK cells and, although they show a relatively normal development of the T cells, they have a more specific T cell defect in which only the preservation of the CD8 T cells is impaired.

People with a defect in the αChain of the IL-7 receptor do not have T cells, but have normal levels of NK cells. This shows that the signals from IL-7 are essential for the development of T cells, but not for the development of NK cells (Fig. 13.2). It is interesting that mice with an artificially created defect in the gene for IL-7R have a T-cell defect like humans, but also have no B cells, which is not the case with humans. This shows the different functions of certain cytokines in the individual species. It is also an indication that care must be taken when interpreting test results in mice and their implications for humans. In humans and mice whose T cells do not produce IL-2 after stimulation of the receptor, the development of the T cells is mostly normal, with the development of FoxP3+-TregCells is disturbed. This can lead to immunoregulatory abnormalities and autoimmunity (Section 10.1007 / 978-3-662-56004-4_15). The rather limited effects of the individual defects in the cytokine signals contrast somewhat with the far-reaching consequences of the development of T and NK cells in X-SCID patients.

As with all severe T cell deficiencies, patients with X-SCID do not produce effective antibody responses to most antigens, and their B cells appear to be normal. Most (but not all) naive IgM-positive B cells from female X-SCID carriers have the defective and not the normal X chromosome inactivated (Section 13.1.3). This shows that the development of B cells depends on the γc-Chain is influenced but not completely dependent on it. In mature B memory cells that have undergone an isotype change, the defective X chromosome is almost without exception inactivated. That could indicate that the γcChain is also part of the receptor for IL-21. This is necessary for the further maturation of B cells after an isotype change (Section 10.1007 / 978-3-662-56004-4_10 # Sec5).

SCID can also be caused by defects in the purine salvage pathway

The variants of the autosomal recessive SCID, which are caused by defects in enzymes of the salvage pathway of purine synthesis, include the Adenosine deaminase deficiency (ADA deficiency , Fig.13.2) and the Purine nucleotide phosphorylase deficiency (PNP deficiency ). Adenosine deaminase catalyzes the conversion of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. This defect leads to the accumulation of deoxyadenosine and its precursor S.-Adenosyl homocysteine, both of which are toxic to T and B cells in the developmental phase. Purine nucleotide phosphorylase catalyzes the conversion of inosine and guanosine to hypoxanthine and guanine, respectively. PNP deficiency is a rarer form of SCID syndrome. It also causes the accumulation of toxic precursors, but has a more severe effect on the development of T cells than on B cells. In both diseases, progressive lymphopenia develops after birth, in which the number of lymphocytes drops sharply, so that these symptoms are already pronounced in the first years of life. Since both enzymes are so-called "household proteins" that are expressed by many cell types, the immunodeficiency that is associated with one of these defects is part of a larger clinical syndrome.

Disturbances in the rearrangement of the antigen receptor genes lead to SCID

Another group of autosomal inherited defects that cause SCID syndrome is caused by failure of DNA rearrangement in developing lymphocytes. Mutations in the RAG-1- or RAG-2Gene to functionless proteins, so that the lymphocyte development of the B and T cells stops in the transition from the pro to the pre cell, since the V (D) J recombination is not carried out correctly (Fig. 13.2). In affected patients, for example, there is a complete lack of T and B cells. As the effects of the RAG-Restricting mutations to the lymphocytes involved in a rearrangement of the antigen receptor genes does not affect the development of the NK cells. There are also children with hypomorphic mutations (which lead to a decrease, but not to the lack of a function) im RAG-1- or in RAG-2Genes that can still produce a small amount of functional RAG protein and thus show minor V (D) J recombinations. This last group includes patients with a very specific and serious disease known as Omenn Syndrome designated. In addition to an increased susceptibility to multiple opportunistic infections, these patients also show clinical features that are very similar to graft-versus-host disease (Section 10.1007 / 978-3-662-56004-4_15 # Sec40) and temporary skin rashes, eosinophilia , Diarrhea, and enlargement of the lymph nodes. Normal or increased numbers of activated T cells are found in these children. One explanation for this phenotype is that a low RAGActivity allows limited recombination of T cell receptor genes. However, there are no B-cells, which suggests that B-cells are more targeted RAG- need activity. Due to the limited number of T-cell receptors, the genes of which have been successfully rearranged, the T-cell repertoire in patients with Omenn's syndrome is severely restricted and the existing limited specificities are cloned to expand. The clinical features strongly suggest that these peripheral T cells are autoreactive and the phenotype of tissue rejection (graft-versus-host-Disease). In addition to the Omenn syndrome, which manifests itself at an early stage in life, other forms of immune deficiency are also related to reduced, but not completely absent, RAG activity. They are often associated with granulomatosis and only appear in late childhood or adolescence.

Another group of patients with autosomal recessive SCID is particularly sensitive to ionizing radiation. Those affected produce very few mature B and T cells because the DNA rearrangement in the developing lymphocytes is faulty. VJ or VDJ linkages rarely occur, and most of them are abnormal. This type of SCID is due to defects in the ubiquitous DNA repair proteins that are involved in repairing double-strand breaks. These occur not only during the rearrangement of the antigen receptor genes (Section 10.1007 / 978-3-662-56004-4_5 # Sec6), but also with ionizing radiation. Due to the patients' increased sensitivity to radiation, the disease is known as RS-SCID (radiation-sensitive SCID) to distinguish them from SCID syndrome due to lymphocyte-specific defects. Defects in the genes of Artemis, DNA-PKcs (DNA protein kinase catalytic subunit) and the DNA ligase IV lead to the RS-SCID (Fig. 13.2). Since defects in the repair of DNA breaks during cell division increase the risk of translocations that can lead to malignant transformations, patients with the various forms of RS-SCID are at an increased risk of cancer.

Defects in signaling by antigen receptors can lead to severe immunodeficiency

Some genetic defects are known that interfere with signaling by T cell receptors (TCRs) and thus block the activation of T cells in an early phase of thymus development. So show patients with mutations in the CD3δ-, CD3ε- or CD3ζChains of the CD3 complex have a defect in pre-T cell receptor signaling and thymus development cannot enter the double positive stage (Fig. 13.2).This leads to the SCID. Another defect in the signaling of lymphocytes, which leads to severe immunodeficiency, is caused by mutations in the tyrosine phosphatase CD45. In humans and mice with a CD45 defect, the number of peripheral T cells is greatly reduced and B cell maturation is abnormal. Serious immunodeficiency also occurs in patients who express a defective form of the cytosolic tyrosine kinase ZAP-70, which normally transmits signals from the T cell receptor (Section 10.1007 / 978-3-662-56004-4_7 # Sec10). Normal numbers of CD4 T cells emerge from the thymus, while CD8 T cells are absent. However, the maturing CD4 T cells cannot respond to signals that normally activate the cells via the T cell receptor.

The Wiskott-Aldrich Syndrome (WHAT) is caused by a defect in the WHATGene on the X chromosome that encodes the WAS protein (WASp). The syndrome provided new insights into the molecular basis of signal transmission in T cells and the formation of immunological synapses between different cells of the immune system. The disease also affects platelets and was first described as a blood clotting disorder. However, it also causes an immune deficiency, which is associated with a reduced number of T cells, a disruption of the cytotoxicity of NK cells and a failure of the antibody response (Section 10.1007 / 978-3-662-56004-4_7 # Sec22). WASp is expressed by all hematopoietic cell lines and is the key regulator in the development of lymphocytes and platelets. The protein transmits receptor-mediated signals and thus causes a restructuring of the cytoskeleton (Section 10.1007 / 978-3-662-56004-4_9 # Sec28). Several signal pathways downstream of the T-cell receptors are known that activate WASp (Section 10.1007 / 978-3-662-56004-4_7 # Sec22). The activation of WASp in turn activates the Arp2 / 3 complex, which is necessary for triggering actin polymerization. This plays a decisive role in the formation of the immunological synapse and the polarized release of effector molecules by the T effector cells. In patients with the WAS syndrome and in mice whose WhatGene has been specifically inactivated, T cells cannot react normally to cross-linking of the T cell receptor. Recently, it has also been suggested that WASp is responsible for the suppressive function of the natural T.regCells is necessary. This may partially explain why patients with WAS syndrome are susceptible to autoimmune diseases.

Genetically determined defects in the thymus function, which block the development of T cells, lead to severe immune deficiencies

A disorder of the thymus development associated with SCID and a lack of body hair has been known in mice for many years. The mutation is named accordingly nude-Mutation the mutant strain is referred to as nude-Trunk (section 10.1007 / 978-3-662-56004-4_8 # Sec13). The same phenotype has been found in a small number of children. In both humans and mice, this syndrome is caused by mutations in the FOXN1Gene that encodes a transcription factor that is selectively expressed in the skin and the thymus. FOXN1 is necessary for the differentiation of the thymus epithelium and the formation of a functional thymus. In patients with a mutation in the FOXN1Gene, the lack of thymus function prevents the normal development of T cells. The development of the B cells is normal in people with this mutation, whereby the lack of T cells means that the B cell reactions are absent and the reactions to almost all pathogens are fundamentally disturbed.

The DiGeorge syndrome is another condition in which the epithelial tissue of the thymus does not develop normally, leading to SCID. The genetic abnormality underlying this complex developmental disorder is a deletion in one copy of chromosome 22. The missing piece is 1.5-5 megabases, with about 24 genes in the shortest form that causes the syndrome. The crucial gene in this section is TBX1, which encodes the T-box transcription factor. DiGeorge syndrome is caused by the lack of a single copy of this gene. The affected patients wear one TBX1-Haploinsufficiency . Without the appropriate, stimulating environment of the thymus, the T cells cannot mature and both the cellular immune response and the T cell-dependent antibody production are impaired. Patients with this syndrome have normal levels of immunoglobulins in their serum, but the thymus and parathyroid glands develop incompletely or not at all, which is associated with varying degrees of T-cell immunodeficiency.

A disturbed expression of the MHC molecules can lead to a severe immune deficiency due to the effects on the positive selection of the T cells in the thymus (Fig. 13.2). In patients with the Naked Lymphocyte Syndrome (bare lymphocyte syndrome) no MHC class II molecules are expressed on the cells; the disease is known today as MHC class II defect . Since there are no MHC class II molecules in the thymus, the CD4 T cells cannot be positively selected, so that only a few mature. The antigen-presenting cells also lack MHC class II molecules, so that the few developing CD4 T cells cannot be stimulated by antigens. Expression of MHC class I molecules is normal and CD8 T cells develop normally. However, those affected suffer from a severe combined immunodeficiency, which underlines the central role of CD4 T cells in adaptive immunity against most pathogens.

The MHC class II deficiency is not due to mutations in the MHC genes, but rather in one of several different genes that encode gene regulatory proteins that are necessary to activate the transcription of the MHC class II genes. Four mutually complementary gene defects (groups A, B, C and D) have now been defined in patients who are unable to express MHC class II proteins. This suggests that at least four different genes are necessary for normal expression of these proteins. Corresponding genes are now known for each complementation group: CIITA (MHC class II transactivator) is mutated in group A, the genes RFXANK , RFX5 and RFXAP are mutated in groups B, C and D (Fig. 13.2). The last three mentioned encode proteins belonging to the multimeric complex RFX, which controls transcription. RFX binds to the X-Box, a DNA sequence in the promoter region of all MHC class II genes.

In a small number of patients, a more limited form of immunodeficiency has been found associated with chronic bacterial infections of the respiratory tract and ulceration of the skin in connection with vascular inflammation. Affected individuals show normal levels of MHC class I mRNA and normal production of MHC class I proteins, but very few of these molecules reach the cell surface. Therefore, the disease is referred to as MHC class I defect . Unlike patients with an MHC class II defect, those affected show normal levels of the mRNA that encodes MHC class I molecules and normal production of MHC class I proteins, but only a few of these proteins achieve the cell surface. The disease can be due to mutations in the TAP1- or in TAP2Gene. These encode the subunits of the peptide transporter that brings the peptides produced in the cytosol into the endoplasmic reticulum, where they are bound to the nascent MHC class I molecules. On the other hand, mutations in the TAPBPGene that encodes tapasin, another component of the peptide transporter complex (Section 10.1007 / 978-3-662-56004-4_6 # Sec5). The reduced number of MHC class I molecules on the surface of the thymus epithelial cells leads to a lack of CD8 T cells (Fig. 13.2), but people with an MHC class I defect are surprisingly not unusual for viral infections vulnerable, although CD8 cytotoxic T cells play a key role in containing viral infections. However, there is evidence of for certain peptides TAP-independent ways of antigen presentation by MHC class I molecules. The clinical phenotype of patients with TAP1- or TAP2-Defekt shows that these pathways can apparently provide a balance so that functional CD8 T cells develop in sufficient numbers to keep viruses in check.

Some defects in the thymus cells cause a phenotype that includes other symptoms in addition to immunodeficiency. The AIREGene encodes a transcription factor that enables thymic epithelial cells to produce many self-proteins so that effective negative selection can take place. Mutations in AIRE-Gen lead to a complex syndrome that one can deal with APECED (Autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy syndrome) and which is associated with autoimmunity, developmental disorders and an immune deficiency (Sect. 10.1007 / 978-3-662-56004-4_8 # Sec27 and Ch. 10.1007 / 978-3-662 -56004-4_15).

When the development of the B cells is disturbed, there is a lack of antibodies, so that extracellular bacteria and some viruses cannot be eliminated

In addition to hereditary defects in proteins that are essential for the development of both T and B cells, for example RAG-1 and RAG-2, defects are now also known that are specific for the development of B cells ( Fig. 13.2). Patients with such defects cannot fight extracellular bacteria and some viruses successfully because specific antibodies are necessary to eliminate them. Pyogenic bacteria, such as staphylococci and streptococci, are surrounded by a polysaccharide shell so that they are not recognized by the receptors on macrophages and neutrophils that stimulate phagocytosis. The bacteria escape destruction by the innate immune response and are successful as extracellular bacteria, but can be eliminated by an adaptive immune response. The opsonization by antibodies and the complement system enables the phagocytes to take up and destroy these bacteria (Section 10.1007 / 978-3-662-56004-4_10 # Sec25). If the antibody production is too low, the main effect is that the immune system can no longer keep infections with pyogenic bacteria at bay. Because antibodies play an important role in neutralizing infectious viruses that enter the body through the intestines, people with decreased antibody production are also particularly susceptible to certain viral infections - especially those caused by enteroviruses.

The first description of an immunodeficiency disease provided Ogden C. Bruton in 1952 using the example of a boy who could not produce antibodies. This defect is inherited with the X chromosome and is characterized by a lack of immunoglobulins in the serum (Agammaglobulinaemia ); it is therefore referred to as X-linked agammaglobulinaemia (X-linked agammaglobulinemia, XLA) or Bruton's syndrome (Fig. 13.2). Since then, different variants of autosomal recessive variants of agammaglobulinaemia have been described. In young children, such diseases can generally be caused by the occurrence of repeated infections with pyogenic bacteria, for example Streptococcus pneumoniae, and detect with enteroviruses. In this context, it should also be noted that normal small children have a temporary deficiency in immunoglobulin production in the first three to twelve months of life. A newborn has antibody levels that are similar to those of the mother because the maternal IgG was transported to the fetus via the placenta (Section 10.1007 / 978-3-662-56004-4_10 # Sec19). As these IgG antibodies are broken down in the metabolism, the antibody levels gradually decrease until the toddler begins to produce sufficient quantities of its own IgG at the age of six months (Fig. 13.3). Therefore, the IgG titers between three months and one year of age are relatively low. This can increase the susceptibility to infections for a while, especially in premature babies. who already have a lower titer of maternal IgG and do not achieve immunocompetence until a long time after birth. Since newborns are temporarily protected by maternal antibodies, the XLA is generally not detected until several months after birth, when the titers of the maternal antibodies have decreased.

The faulty gene in XLA codes for a tyrosine kinase, the so-called Bruton's tyrosine kinase (Btk), which belongs to the family of Tec kinases; these kinases transmit signals from the pre-B cell receptors (pre-BCRs, section 10.1007 / 978-3-662-56004-4_7 # Sec23). As already discussed in Sect. 10.1007 / 978-3-662-56004-4_8 # Sec4, the pre-B-cell receptor consists of heavy ones μChains encoded by a successfully rearranged gene and a complex with the replacement light chain (consisting of λ5 and VpreB) and the signal-transmitting subunits Igα and Igβ form. The stimulation of the pre-B-cell receptor recruits cytoplasmic proteins, including the Btk, which transmit signals necessary for the proliferation and differentiation of B-cells. If the Btk function is missing, the maturation of the B cells is largely blocked in the pre-B cell stage (Fig. 13.2 and Sect. 10.1007 / 978-3-662-56004-4_8 # Sec4). This leads to a fundamental B-cell deficiency and agammaglobulinaemia. However, some B cells mature, possibly because other Tec-Kinases provide a certain balance here.

During embryonic development, one of the two X chromosomes in the cells of the female fetus happens to be inactivated. Since Btk is necessary for the development of B-lymphocytes, only those cells can become mature B-cells in which the normal BTK-Allele is active. According to this, almost all B cells from heterozygous carriers have a mutated one BTKGene activates the normal X chromosome. For this reason, it was possible to identify heterozygous carriers of the XLA defect before the function of the BTKGene product was known. In the T cells and macrophages of such women, however, the X chromosomes are with the normal BTK-Allele and with the mutated allele active with the same probability. The non-random inactivation of the X chromosome, which only occurs in B cells, conclusively proves that Btk is necessary for the development of B cells, but not for that of other cells, and that the enzyme unfolds its effect within the B cells but not in stromal cells or in other cells required for B-cell development (Fig. 13.4).

Autosomal recessive hereditary defects in other components of the pre-B-cell receptor also block B-cell development at an early stage and lead to severe B-cell deficiency and congenital agammaglobulinemia, comparable to the XLA defect. However, these diseases are much less common and can be caused by mutations in the genes that make the disease more severe μ- encode chain (IGHM). This is the second most common cause of agammaglobulinaemia. Other mutations affect λ5 (ILLl1), Igα (CD79A) and Igβ (CD79B) (Fig. 13.2). Mutations affecting the B-cell linker protein used by the BLNKGene encoded signal adapter of the B-cell receptor, also lead to a blockade of B-cell development in an early phase, which causes a selective B-cell deficiency.

Patients with pure B-cell defects can successfully fight many pathogens, apart from pyogenic bacteria. The advantage here is that these infections can be suppressed with the help of antibiotics and periodic infusions with human immunoglobulin, which comes from many different donors. Since the blood collected from many donors contains antibodies against most pathogens, it offers quite good protection against infections.

Immunodeficiencies can be caused by defects in the activation and function of B or T cells that lead to abnormal antibody responses

After their development in the bone marrow or thymus, B and T cells require activation and differentiation triggered by antigens in order to establish an effective immune response. Corresponding to the defects in the early phase of T cell development, errors can also occur during activation and differentiation after selection in the thymus, which affect both cellular immunity and antibody reactions (Fig. 13.5). Defects that specifically affect the activation and differentiation of B cells can impair their ability to isotype-switched to IgG, IgA, or IgE while cellular immunity remains largely intact. Depending on where these defects occur in the process of differentiation of T and B cells, the characteristics of the developing immune deficiency can be fundamental or relatively limited.

One often occurs in patients with a defect that affects B-cell isotype switching Hyper IgM Syndrome (Fig.13.5).These patients show normal B and T cell development and also normal or high IgM levels, but produce few antibody responses to antigens that require T cell support. Therefore, apart from IgM and IgD, other immunoglobulin isotypes are only produced in very small quantities. This makes these patients particularly susceptible to infections with extracellular pathogens. Several different causes are now known for hyper-IgM syndromes. This has contributed to the fact that one could determine the reaction pathways necessary for the normal class change recombination and the somatic hypermutation of the B cells. Defects have been found both in the function of the T helper cells and in the B cells themselves.

The most common form of hyper-IgM syndrome is this X-linked hyper-IgM syndrome , also as CD40 ligand defect which is caused by mutations in the gene for the CD40 ligand (CD154) (Fig. 13.5). The CD40 litand is normally expressed by activated T cells so that they can bind to the CD40 protein on antigen-presenting cells, such as B cells, dendritic cells and macrophages (Section 10.1007 / 978-3-662-56004-4_10 # Sec5). In men with a CD40 ligand deficiency, the B cells are normal, but if CD40 is not bound, the B cells cannot change isotype or initiate the formation of germinal centers (Fig. 13.6). In these patients, with the exception of IgM and IgD, the levels of circulating antibodies are therefore greatly reduced, so that the patients are highly susceptible to infections with pyogenic bacteria.

The CD40 signals are also required for the activation of the dendritic cells and macrophages so that they produce adequate amounts of IL-12, which in turn is essential for the production of IFN-γ through the TH1 and NK cells is needed. Therefore, patients with a CD40 ligand defect also show defective type 1 immunity, which leads to a combined immunodeficiency. If the CD40L-CD40-mediated communication between T cells and dendritic cells is disturbed, the dendritic cells can express fewer co-stimulatory molecules on their surface, so that they stimulate naive T cells less (Section 10.1007 / 978-3-662-56004 -4_9 # Sec19). These patients are therefore susceptible to infections with extracellular pathogens, for example with pyogenic bacteria, the control of which requires antibodies with isotype change. These patients also show defects in the elimination of intracellular bacteria, such as mycobacteria, and they are susceptible to opportunistic infections Pneumocystis jirovecii , a pathogen that is normally killed by activated macrophages.

A similar syndrome occurs in patients who carry mutations in two other genes. It is not necessarily surprising that one of the genes codes CD40, which carries mutations in a few patients with an autosomal recessive variant of the hyper-IgM syndrome (Fig. 13.5). In another form of X-linked hyper-IgM syndrome, also known as NEMO defect , called, mutations occur in the gene that contains the protein NEMO (NFκB essential modulator) encoded, a subunit of the kinase IKK; another name for NEMO is IKKγ . This subunit is an essential part of the intracellular signaling pathway, which is downstream of CD40 and is used to activate the transcription factor NFκB leads (Fig. 10.1007 / 978-3-662-56004-4_3 # Fig15). This group of hyper-IgM syndromes shows that mutations at different points in the CD40L-CD40 signaling pathway lead to similar syndromes of a combined immune defect. Because of the importance of NFκFor many other signaling pathways, the NEMO defect causes additional malfunctions of the immune system that go beyond the disruption of the B-cell isotype change (Sect. 13.1.15). There are also disorders outside of the immune system, such as skin anomalies.

Other variants of the hyper-IgM syndrome can be traced back to intrinsic defects of class change recombination in the B cells. Patients with such defects are susceptible to serious infections with extracellular bacteria, but since the differentiation and function of the T cells are not affected, they are susceptible to intracellular pathogens or opportunistic agents such as P. jirovecii no increased susceptibility. An isotype change defect is caused by mutations in the activation-induced cytidine deaminase (AID) gene, which is necessary for both somatic hypermutation and isotype change (Section 10.1007 / 978-3-662-56004-4_10 # Sec8). Patients with autosomal recessive hereditary mutations in the AID gene (AICDA) cannot change the isotype of their antibodies and show only a very low level of somatic hypermutation (Fig. 13.5). As a result, immature B cells accumulate in abnormal germinal centers and lead to enlargement of the lymph nodes and spleen. Recently, in a few patients with an autosomal recessive defect in the DNA repair enzyme uracil-DNA-glycosylase (UNG; Section 10.1007 / 978-3-662-56004-4_10 # Sec11), another variant of the B- Cell-intrinsic hyper-IgM syndromes discovered. This enzyme also plays a role in the isotype change. The patients show normal AID function and normal somatic hypermutation, but the isotype change is defective.

Other examples of immunodeficiencies that are primarily antibody dependent include the most common forms of primary immunodeficiency, known as variable immunodeficiency syndrome (common variable immunodeficiency, CVID ) or antibody deficiency syndrome. They are a clinically and genetically very heterogeneous group of diseases that are generally not diagnosed before late childhood or adulthood, as the immune deficiency is relatively mild. In contrast to other immune deficiencies, patients with CVID can have defects in immunoglobulin production, which is then limited to one or more isotypes (Fig. 13.5). The most common is IgA defect which occurs in both familial and sporadic forms and is inherited in an autosomal recessive or autosomal dominant manner. The cause of an IgA defect cannot be determined in most patients, and these patients are also symptom-free. IgA-deficient patients who develop recurrent infections usually have an additional defect in one of the IgG subclasses.

A small group of CVID patients carry mutations in the transmembrane protein TACI (TNF-like receptor transmembrane activator and CAML interactor), that of the gene TNFRSF13B is coded. TACI is the receptor for the cytokines BAFF and APRIL, which are produced by T cells, dendritic cells and macrophages and which provide costimulatory and survival signals for the activation and isotype change of B cells (Section 10.1007 / 978-3-662-56004 -4_10 # Sec4). Selective defects of the IgG subclasses have also been found in patients. B-cell counts are generally normal in these patients, but the serum levels of the affected immunoglobulins are greatly reduced. Some of these patients suffer from recurring infections caused by bacteria, as in cases of an IgA defect, but many sufferers are also symptom-free. There are CVID patients with other disorders that affect the immunoglobulin isotype change. This includes patients with an inheritable defect in CD19, a component of the B-cell co-receptor (Fig. 13.5). A genetic disorder that affects only a small group of CVID patients is a deficiency in the costimulatory molecule ICOS. As described in section 10.1007 / 978-3-662-56004-4_9 # Sec19, ICOS is more strongly expressed by activated T cells. The effects of ICOS deficiency have confirmed that ICOS plays a critical role in T cell support during the late stages of B cell differentiation, such as isotype switching and memory cell formation.

Finally in this section we want to deal with the Hyper-IgE Syndrome (HIES) employ that also as Job syndrome referred to as. This disease is associated with recurrent infections of the skin and lungs with pyogenic bacteria, chronic candidiasis of the mucous membranes (a non-invasive fungal infection of the skin and the mucosal surfaces), very high IgE concentrations in the serum and chronic eczematic dermatitis (rash). HIES is inherited as an autosomal recessive or dominant trait, with the latter form causing anomalies of the skeleton and teeth that do not occur in the recessive variant. The hereditary defect of the autosomal dominant HIES variant concerns the transcription factor STAT3, the activation of which is downstream of several cytokine receptors, for example the receptors for IL-6, IL-22 and IL-23. STAT3 is also used in the differentiation of the TH17 cells and the activation of the ILC3 cells are of central importance. The STAT3 signals activated by IL-6 and IL-22 are also important in supporting the antimicrobial defense of the epithelial cells of the skin and mucous membranes. Since in these patients the differentiation of the TH17 cells are disturbed, the neutrophils are not activated either, which is normally done by the TH17 cells is accomplished. Likewise, IL-22 is not produced, a major cytokine that activates the production of antimicrobial peptides by the epithelial cells. It is believed that this defect is responsible for the impairment of the defense against extracellular bacteria and fungi at the epithelial barriers, such as the skin and mucous membranes. The cause of the increased IgE level is not known, but an abnormal activation of the TH2 reactions in the skin and mucous membranes due to the TH17 defect. In an autosomal recessive variant of HIES, the mutation is in the gene for the protein DOCK8 (dedicator of cytokinesis 8), the function of which is little known. However, since DOCK8 is probably more important for T-cell function and for NK-cell function, this HIES variant differs from the STAT3 defects in additional, opportunistic infections and recurring viral infections of the skin (for example, from herpes simplex); there are also allergies and autoimmune reactions.

The normal signaling pathways of the immune defense against various pathogens can be attributed to genetic defects in the cytokine pathways that are responsible for type 1 / TH1- and Type-3 / TH17 responses are central, pinpoint them

Hereditary defects in the cytokines and the associated signaling pathways and receptors that are involved in the development and function of various subsets of the T effector cells have been identified. The aim here is to deal with defects that - unlike those described above - are not associated with serious deficiencies in antibody production. There is a small group of families with some members suffering from persistent and sometimes fatal infections from intracellular pathogens, particularly species of Mycobacterium, Salmonella and Listeriathat are normally prevented by type 1 immunity. These microorganisms specialize in surviving in macrophages and their elimination requires increased antimicrobial activity. These in turn are supported by IFNγ induced by type 1 cells, i.e. NK, ILC1 and TH1 cells, is produced (Section 10.1007 / 978-3-662-56004-4_11 # Sec3). Accordingly, the susceptibility to these pathogens is caused by a number of different mutations that affect the function of IL-12 or IFN-γ, the central cytokines for the development and functioning of type 1 cells, impair or completely block them (Fig. 13.7). Patients have been found to carry mutations in the genes that make up the p40 subunit of IL-12 (IL12B), the β1Chain of the IL-12 receptor (IL12RB1) and the two subunits (R1 and R2) of the IFN-γ-Receptor (IFNGR1 and IFNGR2) encode. Affected individuals are in favor of the more virulent forms of M. tuberculosis more susceptible, but more often get sick from the non-tubercular (atypical) strains of mycobacteria, for example M. avium, probably because these atypical strains are more common in the area. Those affected can also have a vaccination Mycobacterium bovis-Bacillus Calmette-Guérin (BCG) develop a diffuse infection. (M. bovis is used as a live vaccine against M. tuberculosis Because the p40 subunit of IL-12 also belongs to IL-23, an IL-12 p40 defect due to impaired type 1 and type 3 (TH17-) functions to a broader risk of infection (Fig. 13.7). A defect in the IL-12R results accordinglyβ1Chain, which is common to the receptor of IL-12 and IL-23, also leads to a more extensive susceptibility than defects in IFN-γ or the associated receptor.

Autosomal loss of function mutations of STAT1 impair the signaling of the IFN-γReceptor and are also associated with an increased susceptibility to infections with mycobacteria and other intracellular bacteria (Fig. 13.7). Due to the common function of STAT1 in signaling the IFN-α- and the IFN-β-Receptor in response to IFN-α and IFN-β (Type I interferons), patients with a STAT1 defect are also susceptible to viral infections. Interestingly, patients have also been found with only partial loss of STAT1 function who are susceptible to mycobacterial infections, but not to viral infections. This suggests that STAT1 is more necessary to protect against the former.

In addition to the TH17-cell-related defects, which were described above for the hyper-IgE syndrome with STAT3 defect (Sect. 13.1.9), further defects in the cytokine-mediated functions of this signaling pathway have been discovered that do not show any hyper-E symptoms (Fig 13.8). While the increased susceptibility to intracellular bacteria is a common characteristic of immunodeficiencies affecting the type 1 reactions, an increased susceptibility to infection is with Candida spp. and pyogenic bacteria (especially C albicans and S. aureus) characteristic of these type 3 defects. This corresponds to the special function of the T.H17 and ILC3 cells for the defense barriers against fungi and extracellular bacteria. Hereditary defects in IL-17F and IL-17RA, the common receptor component for homo- and heterodimeric IL-17F-IL-17A ligands, lead to susceptibility to these pathogens. This shows the central role of the IL-17 cytokines in the immune defense against these pathogens. Patients with autosomal dominant function gain mutations in STAT1 show a similar susceptibility to chronic candidiasis of the mucous membranes and to pyogenic bacteria. As the development of the TH17 cells are then affected by STAT1 signals downstream of various cytokine receptors (such as type I and type II IFN receptors), those affected show a disruption of their type 3 reactions. This distinguishes them from patients with a STAT1 loss of function mutation, who, due to their defective type I immunity, are predisposed to infections with intracellular bacteria.

In addition to the hereditary defects in the genes of the effector cytokines, autoantibodies against these cytokines are produced in the case of certain immune deficiencies. The resulting infection risks are similar to those with primary cytokine defects. Most patients with APECED syndrome (caused by defects in the AIRE-Gens is evoked; Sect. 13.1.7) develop chronic candidiasis of the mucous membranes, which is due to the production of autoantibodies against IL-17A, IL-17F and / or IL-22. In addition, there are patients with neutralizing antibodies against IFN-γwhose immune protection against infections with atypical mycobacteria is impaired, although the exact cause is unknown.

Hereditary defects in the lymphocyte cytolysis pathways can lead to uncontrolled lymphocyte proliferation and inflammatory reactions in virus infections

Cytolytic granules arise from components of late endosomes and lysosomes. After their formation, further exocytosis steps are required until the cytolytic granules are transferred from the cytotoxic cells to target cells. The importance of immune regulation for the cytolytic reaction pathways is particularly evident in the case of inheritable defects that affect decisive steps either in the formation or in the exocytosis of the cytolytic granules (Fig. 13.9). This leads to a serious and often fatal disease, the hemophagocytic lymphohistiocytosis (HLH syndrome ), which is associated with an uncontrolled activation and proliferation of CD8 T lymphocytes and macrophages. The cells infiltrate several organs and cause necrosis there, which leads to the failure of the organs. This excessive immune response is likely caused by the fact that the cytotoxic cells are unable to target infected cells, and possibly themselves, after an initial viral infection, especially by members of the herpes virus family (such as the Epstein-Barr virus, EBV) , to destroy.In this context, it should be noted that in patients with this disease, despite the impaired release of cytolytic granules, the release of IFN-γ is normally not disturbed by the cytotoxic T lymphocytes (CTLs) and NK cells and this leads to increased activity of the macrophages and the associated inflammation, which in turn is due to the increased release of proinflammatory cytokines such as TNF, IL-6 and M- CSF (macrophage colony stimulating factor) was triggered. The activated macrophages phagocytose blood cells, including erythrocytes and leukocytes (hence the name of the syndrome).

There are a number of autosomal recessive variants of HLH, also known as familial hemophagocytic lymphohistiocytosis (FHL ) designated. They differ in the protein concerned in the cytolytic reaction path (Fig. 13.9). Examples are hereditary defects of the protein perforin in the cytolytic granules, which is necessary for the formation of the pore in the target cell (if there is a defect, FHL2 occurs). Other defects affect the proteins Munc13-4 (FHL3), syntaxin 11 (FHL4), a protein of the SNARE family (SNARE for soluble N-ethylmaleimide-sensitive factor accessory protein receptor), which mediates membrane fusion, and Munc18-2 (FHL5), which helps restructure the SNARE complex to activate the fusion process. Since components of the biogenesis and exocytosis of the cytolytic granules also occur in other secretory vesicles, for example in the lysosomes, other immune defects as well as nonimmune defects can occur in affected persons. For example, some immune deficiencies, in which the function of the cytolytic granules is impaired, are accompanied by a partial loss of skin pigmentation. This is due to defects in the proteins for vesicle transport, which are also required for the exocytosis of the melanosomes (organelles that store the skin pigment melanin in the melanocytes). These are examples of these immune deficiencies Chediak-Higashi Syndrome caused by mutations in the CHS1 protein that regulates lysosomal transport, and the Griscelli syndrome , which is caused by mutations in the gene for the small GTPase RAB27a (Fig. 13.9), which is essential for the attachment of certain vesicles, including the cytolytic granules, to the structures of the cytoskeleton, as this is the only way to enable their intracellular transport.

In patients with Chediak-Higashi syndrome, giant forms of lysosomes and granules accumulate in the T lymphocytes, myeloid cells, platelets, and melanocytes. The hair of those affected has a silver metallic shimmering color, the eyesight is severely restricted due to the abnormal pigment cells in the retina and the malfunction of the blood platelets leads to increased bleeding. Since the vesicle fusion of the phagocytes is also disturbed in these patients, intracellular and extracellular pathogens cannot be killed effectively, and the cytolytic function of the CTL and NK cells is also defective. Affected children therefore suffer from serious recurring infections from various bacteria and fungi at an early age. Thereafter, hemophagocytic lymphohistiocytosis generally develops, which is often triggered by a viral infection, for example with EBV, which then accelerates the disease even further. Three variants of Griscelli syndrome are known, each of which is triggered by a different genetic defect. With the type 2 variant (mutation in RAB27A ) the defect leads to both an immunodeficiency and pigment anomalies, with types 1 and 3 only pigment anomalies occur. The immunodeficiencies in children with Griscelli syndrome type 2 resemble the Chediak-Higashi syndrome in many ways, but there are no giant granules in the myeloid cells.

X-linked lymphoproliferative syndrome is associated with fatal Epstein-Barr virus infection and the development of lymphomas

Some primary immunodeficiency diseases are susceptible to only one specific pathogen. This is the case with two rare X-linked immunodeficiencies, each characterized by a similar lymphoproliferative defect caused by a virus of the herpes simplex family - the Epstein-Barr virus (EBV), whereby the mechanisms are different. EBV specifically infects the B cells and causes a self-limiting infection in otherwise healthy individuals, since the virus expresses the EBV antigens through the activities of the NK, NKT and cytotoxic T cells, which are specific for B cells , is brought under control. Once immunity against EBV has developed, the virus is not completely eliminated, but remains in a latent form in the B cells (Sect. 13.2.6). With certain types of immune deficiency, this control can be lost, leading to excessive EBV infection (severe infectious mononucleosis), which leads to an unregulated proliferation of EBV-infected B cells and cytotoxic T cells, hypogammaglobulinemia (low Circulating immunoglobulins). This puts you at risk of developing non-Hodgkin lymphomas. These occur with the rare immunodeficiency X-linked lymphoproliferative (XLP-)Syndrome on. The XLP syndrome results from mutations in one of the two X-linked genes SH2D1A (SH2 domain-containing gene 1A) and XIAP. The former encodes SAP (signaling lymphocyte activation molecule (SLAM)associated protein), The latter encodes the X-coupled apoptosis inhibitor.

In XLP1 syndrome, which affects around 80% of patients with one of the two syndromes, the SAP defect leads to the coupling between the immune cell receptors of the SLAM family and the Tyrosine kinase Fyn from the Src family is lost (Fig. 13.10