Innate immune disorders

Several intermediate proteins take part in the process of sending signals sensed by TLRs to the nucleus. All TLRs, except TLR3, use myeloid differentiation primary response protein 88 (Myd88) as an adaptor (partner) protein. Since Myd88 recruits and interacts with another protein called interleukin-1 receptor-associated kinase 4 (IRAK-4) in the signaling pathway, genetic variants in either Myd88 or IRAK-4 result in the same invasive infections with pus-inducing (pyogenic) bacteria. Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa are the most common bacteria to cause infections in these individuals. Infections are usually severe (sepsis, meningitis, arthritis, osteomyelitis, abscesses), particularly during the first years of life. Of note, immune responses to other types of bacteria, viruses, fungi, and parasites are unaffected.

Despite having severe infections, individuals with Myd88 or IRAK 4 deficiencies commonly present only with low-grade fever and slightly abnormal inflammatory markers, like a sedimentation rate or c-reactive protein (CRP). Diagnosing these defects can be tricky, as most routine immunological tests are normal. Some individuals show abnormal antibody responses to polysaccharide antigens and elevated serum levels of IgE. Specialized laboratories can run specific tests to evaluate TLR function, but a definitive diagnosis relies on genetic testing.

Infection severity for these individuals decreases with age, once other arms of the immune system mature and take control of the troublesome pathogens. However, early-life infections can be life-threatening and require careful management. Caregivers and healthcare professionals must be prepared to provide immediate and aggressive treatment for infections despite mild symptoms. Most of these individuals benefit from prophylactic antibiotics, and some might need temporary immunoglobulin (Ig) replacement therapy. 

Individuals with TLR3 deficiency, the only TLR that does not signal through Myd88, are at increased risk of developing herpes simplex virus (HSV-1) encephalitis, a severe viral infection of the brain and central nervous system. It typically occurs in childhood, when individuals first encounter this virus (HSV-1 is the most common cause of cold sores). Infection susceptibility is restricted to HSV-1, as individuals can mount effective responses against other viruses, bacteria, and fungi. 

HSV-1 encephalitis is a rare infection and should prompt investigation for immunodeficiency. Other genes related to TLR3 signaling, such as UNC93B1, TRIF, TRAF, and TBK1, must also be screened. Mortality rates associated with these diseases are high (around 70%) when untreated. However, outcomes can improve using antivirals, interferons, and supportive care. 

In the chain of chemical reactions after TLR activation, NF-kappa-B essential modulator (NEMO) is an important protein downstream of Myd88 and IRAK-4. NEMO is required for the activation of the NF-kappa-B family of transcription factors. These factors ultimately regulate lymphocyte development and proliferation, inflammation, and immune responses.

Besides TLRs, other signaling pathways also recruit NEMO. For this reason, in NEMO deficiency, many cellular processes are affected, and individuals tend to have more clinical manifestations compared to TLR deficiencies. 

One of these pathways starts with the ectodysplasin-A receptor, which is important for the development of ectodermal tissues, such as hair, skin, nails, etc. Malfunction of this pathway results in anhidrotic ectodermal dysplasia (EDA), a condition characterized by dry and thickened skin, conical teeth, absence of sweat glands, and thin, sparse hair. About 90% of individuals with NEMO deficiency have EDA. Several different disorders can cause EDA, but the association of EDA and immune deficiency (EDA-ID) is highly suggestive of NEMO deficiency syndrome.

From the immunological standpoint, individuals with NEMO deficiency syndrome have a range of infections with pus-inducing organisms. Streptococcus pneumonia and Staphylococcus aureus are the most common pathogens, but individuals with NEMO can also have viral and fungal infections. Infections can be severe and may be found virtually anywhere in the body, including the lungs, skin, central nervous system, liver, abdomen, urinary tract, bones, and gastrointestinal tract. 

Despite vaccination, many individuals have humoral immunity problems with a complete lack of antibody response against certain bacteria, such as Streptococcus pneumoniae. A subset of these individuals presents with high serum levels of IgM. Other individuals exhibit deficiencies in additional arms of the immune system that cause increased susceptibility to mycobacteria. These individuals may develop disseminated infection if they receive the BCG vaccine (the live tuberculosis vaccine, which is not used in the U.S. but is commonly given in other countries).

A small group of individuals has a more severe disease course presenting with two additional conditions: osteopetrosis (a disorder in which bones are denser, prone to fractures, and the bone marrow fails to produce blood cells) and lymphedema (fluid retention due to defects in lymphatic vessels), known as OL-EDA-ID syndrome.

NEMO deficiency is inherited in an X-linked manner; hence, almost all cases occur in boys. Female carriers are normally free of immune symptoms, but some might have a skin condition called incontinentia pigmenti.

Diagnosis of NEMO deficiency is based on clinical manifestations. The presence of EDA is usually a hint but can be absent in 10% of individuals. Almost all individuals with NEMO deficiency lack protective levels of pneumococcal antibodies following pneumococcal vaccination. Routine immunological tests are variable among individuals, and normal results do not rule out the diagnosis. Diagnostic confirmation requires genetic testing.

Therapy for NEMO deficiency aims to prevent infections and complications stemming from infection. Individuals with antibody defects receive immunoglobulin (Ig) replacement therapy. While this therapy is a cornerstone of treatment, it is insufficient alone to control infections, given the broad-based immune issues in these individuals. Therefore, individuals also receive a series of prophylactic antibiotics as part of their infection-preventive regimen.

Individuals with NEMO deficiency should see their primary care physician and immunologist regularly, as problems and complications can be frequent. Treatment should be started promptly whenever an infection is suspected. Hematopoietic stem cell transplantation (HSCT) has been used for some individuals with NEMO deficiency. Outcomes after transplantation have been variable. Transplantation can correct the immunological defects of NEMO deficiency but does not improve the other complications of the syndrome.

Learn more about NEMO deficiency

NK cells are innate immune cells important in the killing of cancer cells or cells that have been infected by viruses. NK cells are so named because they can kill cells without the need for any pre-training. They are present in relatively low numbers in the bloodstream and tissues.

NK cells kill virus-infected cells by poking holes in the cells’ membranes and injecting toxic proteins into the viral-infected cells. NK cells are particularly important in the defense against herpes viruses. This family of viruses includes herpes simplex virus (HSV), which causes cold sores and genital herpes, Epstein-Barr virus (EBV), which causes infectious mononucleosis, cytomegalovirus (CMV), and varicella-zoster virus (VZV), the cause of chicken pox and shingles. Individuals with NK cell deficiency present with severe or recurrent infections caused by herpes viruses and papillomaviruses, which can cause warts and cancer.

Human NK cell deficiencies have been divided into two categories:

1. Quantitative defects: with absent or very low numbers of NK cells in the peripheral blood. 
2. Qualitative defects: with normal numbers of NK cells but abnormal NK cell function

NK cell deficiencies in the first category are called classical NK cell deficiencies and those in the second category are functional NK cell deficiencies.

Diagnosis includes quantification of NK cells, as well as assessment of function (ability to kill target cells). Several medications and disease processes may have an impact on NK cell numbers and activity. Therefore, abnormal tests should be repeated on separate occasions to establish the diagnosis. Genetic causes of NK cell deficiency have been identified, including autosomal recessive and dominant forms.

Vaccination against human papillomavirus (HPV) is recommended. Some individuals might need continuous use of antiviral agents and may benefit from immunoglobulin (Ig) replacement therapy. More specific therapies are under study. For individuals with severe disease, hematopoietic stem cell transplantation (HSCT) might be considered. 

Macrophages (“big eaters” in Greek) are innate immune cells found in all human tissues. They are able to kill microbes by eating and subsequently digesting them. However, some pathogens, such as Mycobacterium and Salmonella, learned how to escape from destruction and became capable of surviving and growing within macrophages. To overcome this, macrophages produce IL-12 to activate specialized T and NK cells and stimulate interferon-γ (IFN-γ) production, which acts on macrophages leading to the killing of intracellular microbes. This cooperation represents the IFN-γ/IL-12 pathway. Rare genetic variants affecting this pathway have been described and are collectively called Mendelian susceptibility to mycobacterial disease (MSMD).

The hallmark of MSMD is susceptibility to mycobacteria (the family of bacteria that causes tuberculosis and related infections) and Salmonella infections, with some individuals also suffering from viral, fungal, and parasitic infections. Many of the affected individuals become ill in infancy after receiving the live anti-tuberculosis BCG vaccine, which is not used in the U.S. but is commonly given in other countries. 

Other individuals have skin infections, swollen lymph nodes, or bloodstream infections later in life upon encountering Mycobacterium tuberculosis or other environmental nontuberculous mycobacteria (NTM) that are not harmful to healthy individuals.

In about half of cases, the genetic cause of MSMD is not known. Some individuals presenting with adult-onset infections resembling MSMD do not have genetic variants in the IFN-γ/IL-12 pathway but rather have autoantibodies directed against interferon-γ.

Once MSMD is suspected, diagnosis can be sought by investigating whether the components (proteins) involved in the IFN-γ/IL-12 pathway are present and/or functioning. For that reason, sometimes, specific tests to assess function are needed. Genetic testing can confirm the diagnosis.

Individuals with MSMD should not receive BCG or live Salmonella vaccines, as complications can be life-threatening. Treatment of infections consists of prolonged courses of antibiotics, and surgical procedures are sometimes required. Depending on their deficiency, IFN-γ replacement can benefit some, but not all, individuals with MSMD. Once infections are cleared, prophylactic antibiotics are usually prescribed. Hematopoietic stem cell transplantation (HSCT) is restricted to severe cases, given that rejection rates after transplant in these individuals are high.